Methods of drug loading a hollow stent by immersion

ABSTRACT

A method of loading a composition into a structural element of a stent, where the structural element is defined by a lumen and at least one opening to access the lumen. The structural element, or a stent having such a structural element, is immersed in a solution or a composition, and the composition or solution is allowed to fill the lumen. The composition or solution may comprise a therapeutic agent.

CROSS REFERENCE TO RELATED APPLICATION

This application is a divisional application of U.S. patent applicationSer. No. 13/035,813, filed on Feb. 25, 2011, and published as UnitedStates Patent Application Publication Number US 2012-0216908 A1, on Aug.30, 2012, which is incorporated by reference herein in its entirety,including any drawings, and which is incorporated by reference hereinfor all purposes.

FIELD OF THE INVENTION

This invention relates to methods of depositing a composition within astructural element of a stent and various types of apparatus used insuch methods.

BACKGROUND OF THE INVENTION

The discussion that follows is intended solely as background informationto assist in the understanding of the invention herein; nothing in thissection is intended to be, nor is it to be construed as, prior art tothis invention.

Until the mid-1980s, the accepted treatment for atherosclerosis, i.e.,narrowing of the coronary artery(ies), was coronary by-pass surgery.While effective and evolved to a relatively high degree of safety forsuch an invasive procedure, by-pass surgery still involves seriouspotential complications, and in the best of cases, an extended recoveryperiod.

With the advent of percutaneous transluminal coronary angioplasty (PTCA)in 1977, the scene changed dramatically. Using catheter techniquesoriginally developed for heart exploration, inflatable balloons wereemployed to re-open occluded regions in arteries. The procedure wasrelatively non-invasive, took a very short time compared to by-passsurgery and the recovery time was minimal. However, PTCA brought with itanother problem, elastic recoil of the stretched arterial wall whichcould undo much of what was accomplished and, in addition, PTCA failedto satisfactorily ameliorate another problem, restenosis, there-clogging of the treated artery.

The next improvement, advanced in the mid-1980s, was use of a stent tohold the vessel walls open after PTCA. This for all intents and purposesput an end to elastic recoil but did not entirely resolve the issue ofrestenosis. That is, prior to the introduction of stents, restenosisoccurred in 30-50% of patients undergoing PTCA. Stenting reduced this toabout 15-30%, much improved but still more than desirable.

In 2003, the drug-eluting stent (DES) was introduced. The drugsinitially employed with the DES were cytostatic compounds, compoundsthat curtailed the proliferation of cells that contributed torestenosis. As a result, restenosis was reduced to about 5-7%, arelatively acceptable figure. Today, the DES is the default industrystandard for the treatment of atherosclerosis and is rapidly gainingfavor for treatment of stenoses of blood vessels other than coronaryarteries such as peripheral angioplasty of the popliteal artery.

The DES used today have a drug-polymer coating on the exterior surfaceof the stent. The inclusion of the drug in a polymer matrix allows forsustained delivery over time. One of the limitations of DES is theamount of drug that may be contained in a coating on a device. Anotherpotential drawback is that the polymers used in the coating maycontribute to an inflammatory response when the stent is implanted.Depending on the mechanical properties of the coating, it may becomedamaged during aggressive delivery procedures such as treating calcifiedlesions, or delivering the DES through a previously deployed stent.Also, the crimping of a DES onto a delivery device, such as the balloonof a catheter, must be done carefully to avoid damaging the coating.

Some alternatives to DES are stents with depots or channels in thestructural elements, or struts, of the stent, or stents with somestructural elements that are hollow tubes. Therapeutic agents or acomposition including therapeutic agents may fill the interior of thehollow tube or a channel or depots. However, there are a number ofchallenges involved with filling such a hollow stent or depots with acomposition including a therapeutic agent.

There is a continuing need for methods of filling the interior of ahollow structural element of a stent and one or more types of apparatusthat may be used in such methods.

SUMMARY OF THE INVENTION

The present invention is directed to methods of loading a compositioninto a structural element of a stent. The methods include the operationsof providing a stent having a structural element or providing astructural element that is to be used in forming a stent, the structuralelement defined by a lumen and at least one opening to access the lumen;providing a container filled with a composition or a solution; immersingthe structural element into the solution or the composition; andallowing the solution or the composition to fill the lumen. If asolution fills the container, the solution is in a liquid or asupercritical fluid state, the solution includes a solvent and acomposition including a therapeutic agent, and the solvent having aboiling point of less than 20° C. at 1 atmosphere, and the solution ismaintained under a condition of temperature and pressure that maintainsthe solution in a liquid or a supercritical fluid state. If a solutionfills the container, after allowing the solution to fill the lumen, thecondition of temperature and pressure is adjusted to evaporate thesolvent thereby leaving the composition comprising the therapeutic agentin a solid state, or a semi-solid state, or a fluid state having aviscosity of at least 100 cP, within the lumen.

The methods may also include any one or more of the following aspects tothe extent that the various aspects may be combined.

In an aspect of the present invention, the structural element is removedfrom the solution and the solvent is allowed to evaporate, therebyleaving a composition remaining within the lumen, the composition beingin a fluid state having a viscosity of at least 100 cP.

In an aspect of the present invention, after the solvent has evaporated,the composition remaining in the lumen is in a solid state, or asemi-solid state.

In an aspect of the present invention, the method further includes,after allowing the solution to fill the lumen before adjusting thecondition, removing the structural element from the solution.

In an aspect of the present invention, the method further includessealing the access opening when the structural element is removed fromthe solution to prevent the solution from escaping out from the lumen.

In an aspect of the present invention, method further includes removingthe seal after the solvent has evaporated.

In an aspect of the present invention, the method further includesexecuting at least one additional time the cycle of immersing thestructural element, allowing the solution to fill the lumen, andadjusting the condition.

In an aspect of the present invention, adjusting the condition includesincreasing the temperature to about 20° C. or greater than 20° C.

In an aspect of the present invention, adjusting the condition includesdecreasing the pressure to about one atmosphere or less than oneatmosphere.

In an aspect of the present invention, adjusting the condition includesdecreasing the pressure to about one atmosphere or less than oneatmosphere, and increasing the temperature to about 20° C. or greaterthan 20° C.

In an aspect of the present invention, further including rinsing thestructural element to at least partially remove the compositioncomprising the therapeutic agent on an exterior surface of thestructural element such that the rinsing act does not remove thecomposition comprising the therapeutic agent from within the lumen.

In an aspect of the present invention, the structural element is a tubesuch that the access opening is positioned at one end of the tube andthe tube further comprises a plurality of discharge openings about asurface of the tube to allow discharge of the composition comprising thetherapeutic agent from the structural element after implantation of thestent.

In an aspect of the present invention, the method additionallyincluding, prior to the immersion, attaching a conduit to the accessopening, and applying a vacuum through the access opening via theconduit when the structural element is immersed in the solution to drawthe solution through the discharge openings into the lumen.

In an aspect of the present invention, each of the discharge openings ofthe structural element is at most 50% of the size of the access openingof the structural element.

In an aspect of the present invention, the method further includingcooling the structural element to a temperature of about 20° C. or lessthan 20° C. before immersion to assist with the solution penetrationinto the lumen.

In an aspect of the present invention, the composition of the solutionincludes an additive or an excipient and the additive or the excipientcauses the solution to have a contact angle of less than 90 degrees onthe surface of the structural element to allow the solution to penetrateinto the lumen with greater ease than if the additive were not present.

In an aspect of the present invention, the composition of the solutionincludes a wetting enhancement fluid which allows the solution to have acontact angle of less than 90 degrees on the surface of the structuralelement to allow the solution to penetrate into the lumen with greaterease than if the wetting enhancement fluid were not present.

In an aspect of the present invention, the solvent of the solution has aboiling point at one atmosphere of 0° C. or less than 0° C.

In an aspect of the present invention, the solvent of the solution has aboiling point at one atmosphere of −10° C. or less than −10° C.

In an aspect of the present invention, the solvent is selected of thesolution from the group consisting of pentane, cyclopentane, butane,propane, dimethylether, trifluoromethane, dichlorodifluoromethane,chlorodifluoromethane, 1,2-dichloro-1,1,2,2-tetrafluoro ethane,1-chloro-1,1-difluoroethane, 1,1,1,2-tetrafluoroethane (HFC-134a),1,1,1,2,3,3,3-heptafluoropropane (HFC-227) freons, carbon dioxide, andcombinations in all proportions thereof.

In an aspect of the present invention, the therapeutic agent of thecomposition is selected from the group consisting of paclitaxel,protaxel, clobetasol, dexamethasone, momentasone, dexamethasone acetate,zotarolimus, sirolimus, everolimus, biolimus, deforolimus, novolimus,myolimus, temsirolimus, and any combination thereof.

In an aspect of the present invention, the container is filled with acomposition, the composition comprising a therapeutic agent, and whereinthe composition is in a fluid state in the container, and thecomposition has characteristics such that when the composition is at atemperature of 30° C. and at one atmosphere, the composition is in asolid state or semi-solid state or in a fluid state with a viscosity ofabout 10 cP or greater than 10 cP; or the composition hascharacteristics such that when the composition is at a temperature of20° C. to 30° C. and a pressure of one atmosphere, the viscosity of thecomposition is greater than 10 cP or about 10 cP.

In an aspect of the present invention, the method further includingafter allowing the composition to fill the lumen, removing thestructural element from the composition.

In an aspect of the present invention, the method further includessealing the access opening when the structural element is removed fromthe composition to prevent the composition from escaping out from thelumen.

In an aspect of the present invention, the method further includingrinsing the structural element to at least partially remove thecomposition comprising the therapeutic agent on an outer surface of thestructural element such that the rinsing act does not remove thecomposition comprising the therapeutic agent from within the lumen.

In an aspect of the present invention, the structural element is a tubesuch that the access opening is positioned at one end of the tube andthe tube further comprises a plurality of discharge openings about asurface of the tube to allow discharge of the composition comprising thetherapeutic agent from the structural element after implantation of thestent in a patient.

In an aspect of the present invention, the method further includes,prior to the immersion, attaching a conduit to the access opening, andapplying a vacuum through the access opening via the conduit when thestructural element is immersed in the composition to draw thecomposition through the discharge openings into the lumen.

In an aspect of the present invention, each of the discharge openings ofthe tube is at most 50% of the size of the access opening.

In an aspect of the present invention, the composition in the containeris free of, or essentially free of, solvents, and the composition is ina fluid state in the container, and the composition has characteristicssuch that when the composition is at a temperature of 30° C. and at oneatmosphere, the composition is in a solid state or a semi-solid state orin a fluid state with a viscosity of not less than 10 cP.

In an aspect of the present invention, the composition is free of, oressentially free of, solvents, and the composition is in a fluid statein the container, and the composition has characteristics such that whenthe composition is at a temperature of 30° C. and at one atmosphere, thecomposition is in a solid state or a semi-solid state or in a fluidstate with a viscosity of not less than 100 cP.

In an aspect of the present invention, the composition in the containeris free of, or essentially free of, solvents, and the composition is ina fluid state in the container, and the composition has characteristicssuch that when the composition is at a temperature of 30° C. and at oneatmosphere, the composition is in a solid state or a semi-solid state.

In an aspect of the present invention, the method further includingheating the structural element to a temperature of about 30° C. to about60° C. prior to immersion into the composition.

In an aspect of the present invention, the method further includes,after allowing the composition to fill the lumen, cooling the structuralelement.

In an aspect of the present invention the composition consistsessentially of the therapeutic agent.

In an aspect of the present invention, the therapeutic agent of thecomposition is relatively stable or stable in the melt.

In an aspect of the present invention, the therapeutic agent of thecomposition is selected from the group consisting of paclitaxel,protaxel, dexamethasone, momentasone, clobetasol, dexamethasone acetate,and combinations thereof.

In an aspect of the present invention, the composition comprises anexcipient.

In an aspect of the present invention, the therapeutic agent of thecomposition is temperature sensitive.

In an aspect of the present invention, the therapeutic agent is notstable at temperatures of about 60° C. and greater than 60° C.

In an aspect of the present invention, the therapeutic agent of thecomposition is selected from the group consisting of zotarolimus,everolimus, sirolimus, biolimus, deforolimus, novolimus, myolimus,temsirolimus, and combinations thereof.

In an aspect of the present invention, the excipient is selected fromthe group consisting of solid poloxamers, polysorbate 60, Vitamin ETGPS, di-block and tri-block polymers formed from ethylene oxide andpropylene oxide, Poloxamer 188, Poloxamer 407, ascorbyl palmitate,lecithin, egg yolk phospholipid, phosphatidylcholine, polyethyleneglycol-phosphatidyl ethanolamine conjugate (PEG-PE), polyethyleneglycol, triglycerides, diglycerides, monoglycerides, fatty alcohols, andany combination thereof.

In an aspect of the present invention, the composition is free of, oressentially free of, solvents, and the composition has characteristicssuch that when the composition is at a temperature of 20° C. to 30° C.and a pressure of one atmosphere, the viscosity of the composition isgreater than 100 cP or about 100 cP.

In an aspect of the present invention, the composition hascharacteristics such that that when the composition is at a temperatureof 20° C. to 30° C. and a pressure of one atmosphere, the viscosity ofthe composition is equal to or greater than 5000 cP but not more than5000 cP.

In an aspect of the present invention, the composition comprises anexcipient.

In an aspect of the present invention, the therapeutic agent isdispersed in the excipient.

In an aspect of the present invention, the composition comprisesmicrospheres, nanoparticles, microparticles, and/or microshells whichcomprise the therapeutic agent.

DESCRIPTION OF THE DRAWINGS

FIG. 1A depicts an exemplary and non-limiting embodiment of a stent withhollow struts.

FIG. 1B depicts a close-up of a hollow strut of an exemplary embodimentof a stent.

FIG. 2 depicts an exemplary injector.

FIGS. 3A-3D depict several methods of coupling an injector to a tube.

FIGS. 4A and 4B depict a device for sealing openings in hollow struts ofa stent.

FIGS. 5A-5C depict a device for use when injecting a composition intothe lumen of a stent with hollow struts.

FIGS. 5D and 5E depict the internal and external pressure gradients,respectively, in the device of FIGS. 5A-5C.

FIG. 6 depicts a system for filling the interior of a stent with hollowstruts.

FIG. 7 depicts another system for filling the interior of a stent withhollow struts.

FIGS. 8A and 8B depict the end view of an open tube, and the end view ofa tube that has been crimped.

FIGS. 9A, 9B, and 9C depict two exemplary plugs and an exemplary cap.

DETAILED DESCRIPTION

Use of the singular herein includes the plural and vice versa unlessexpressly stated to be otherwise. That is, “a” and “the” refer to one ormore of whatever the word modifies. For example, “a stent” may refer toone stent, two stents, etc. Likewise, “the polymer” may mean one polymeror a plurality of polymers. By the same token, words such as, withoutlimitation, “stents” and “polymers” would refer to one stent or polymeras well as to a plurality of stents or polymers unless it is expresslystated or obvious from the context that such is not intended.

As used herein, words of approximation such as, without limitation,“about,” “substantially,” “essentially,” and “approximately” mean thatthe word or phrase modified by the term need not be exactly that whichis written but may vary from that written description to some extent.The extent to which the description may vary from the literal meaning ofwhat is written, that is the absolute or perfect form, will depend onhow great a change can be instituted and have one of ordinary skill inthe art recognize the modified version as still having the properties,characteristics and capabilities of the modified word or phrase. Ingeneral, but with the preceding discussion in mind, a numerical valueherein that is modified by a word of approximation may vary from thestated value by ±15%, unless expressly stated otherwise.

As used herein, any ranges presented are inclusive of the end-points.For example, “a temperature between 10° C. and 30° C.” or “a temperaturefrom 10° C. to 30° C.” includes 10° C. and 30° C., as well as anytemperature in between.

As used herein, a “polymer” refers to a molecule comprised of, eitheractually or conceptually, repeating “constitutional units.” Theconstitutional units may derive from the reaction of monomers. As anon-limiting example, ethylene (CH₂═CH₂) is a monomer that can bepolymerized to form polyethylene, CH₃CH₂(CH₂CH₂)₁CH₂CH₃, wherein nrepresents an integer, and the constitutional unit is —CH₂CH₂—, ethylenehaving lost the double bond as the result of the polymerizationreaction. A polymer may be derived from the polymerization of severaldifferent monomers and therefore may comprise several differentconstitutional units. Such polymers are referred to as “copolymers.” Theconstitutional units themselves can be the product of the reactions ofother compounds. As used herein, a molecule of more than 20constitutional units is a polymer. Those skilled in the art, given aparticular polymer, will readily recognize the constitutional units ofthat polymer and will equally readily recognize the structure of themonomer from which the constitutional units derive. A polymer may be alinear chain, a branched chain, star-like or dendritic, or one polymermay be attached (grafted) onto another. Polymers may have a randomdisposition of constitutional units along the chain, the constitutionalunits may be present as discrete blocks, or constitutional units may beso disposed as to form gradients of concentration along the polymerchain. Polymers may be cross-linked to form a network.

An “oligomer” is a molecule comprised of, either actually, orconceptually, repeating constitutional units, but where the number ofconstitutional units is too small to be considered to be a polymer. Asused herein, an oligomer is a molecule of 20 or fewer constitutionalunits.

As used herein, “biocompatible” refers to a material that both in itsintact, that is, as synthesized, state and in its decomposed state,i.e., its degradation products, is not, or at least is minimally, toxicto living tissue; does not, or at least minimally and reparably,injure(s) living tissue; and/or does not, or at least minimally and/orcontrollably, cause(s) an immunological reaction in living tissue.

As used herein, the terms bioresorbable, biodegradable, bioabsorbable,bioerodable, biosoluble, absorbable, and resorbable, as well asdegradable, erodable, and dissolvable, are used interchangeably, andrefer to materials that are capable of being completely eroded,degraded, either biodegraded and/or chemically degraded, and/or absorbedwhen exposed to bodily fluids, such as blood, and can be graduallyresorbed, absorbed and/or eliminated by the body.

Conversely, a “biostable” material refers to a material that is notbiodegradable.

As used herein, an “implantable medical device” refers to any type ofappliance that is totally or partly introduced, surgically or medically,into a patient's body or by medical intervention into a natural orifice,and which is intended to remain there after the procedure. The durationof implantation may be essentially permanent, i.e., intended to remainin place for the remaining lifespan of the patient; until the devicebiodegrades; or until it is physically removed.

One form of implantable medical device is a “stent.” A stent refersgenerally to any device used to hold tissue in place in a patient'sbody. Stents may be typically tubular shaped devices. Particularlyuseful stents, however, are those used for the maintenance of thepatency of a vessel in a patient's body when the vessel is narrowed orclosed due to diseases or disorders including, without limitation,tumors (m, for example, bile ducts, the esophagus, the trachea/bronchi,etc.), benign pancreatic disease, coronary artery disease such as,without limitation, atherosclerosis, carotid artery disease, peripheralarterial disease, restenosis and vulnerable plaque.

A “lumen” as defined by Webster's Medical Dictionary is the channelwithin a tube such as a blood vessel, or the interior of a hollow organsuch as the intestine. The term lumen is usually an anatomical term. Asused herein, the term “lumen” may be broader, and may not only refer tothe anatomy of an animal, but may also refer to the channel inside atube or a tubular shaped object.

As used herein, a “hole” is an opening or a channel in a materialcreated by any one or more of a combination of etching, laser machining,mechanical machining, drilling, and conventional processes known bypersons of ordinary skill in the art. The location of holes may bepredetermined.

As used herein, a “pore” is an opening or channel in a material thatnaturally results from the properties of the material. The location ofpores may not be pre-determined.

As used herein, the terms “pores” and “holes” will be usedinterchangeably unless expressly stated otherwise.

As used herein, a material that is described as a layer or a film (e.g.,a coating) “disposed over” an indicated substrate refers to a coating ofthe material deposited directly or indirectly over at least a portion ofthe surface of the substrate. “Directly deposited” means that thecoating is applied directly to the surface of the substrate. “Indirectlydeposited” means that the coating is applied to an intervening layerthat has been deposited directly or indirectly over the substrate. Theterms “layer”, and “coating layer” will be used interchangeably andrefer to a layer or film as described in this paragraph. A coating maybe one layer or more than one layer. Each layer may be formed by one ormultiple applications of coating material. A coating and a coating layerare supported by the substrate. Unless the context clearly indicatesotherwise, a reference to a coating, layer, or coating layer refers to alayer of material that covers all, or substantially all, of the surface,whether deposited directly or indirectly.

As used herein, a “therapeutic agent” refers to any substance that, whenadministered in a therapeutically effective amount to a patientsuffering from a disease or condition, has a therapeutic beneficialeffect on the health and well-being of the patient (an animal, includinga human). A therapeutic beneficial effect on the health and well-beingof a patient includes, but it not limited to: (1) curing the disease orcondition; (2) slowing the progress of the disease or condition; (3)causing the disease or condition to retrogress; or, (4) alleviating oneor more symptoms of the disease or condition.

As used herein, a therapeutic agent also includes any substance thatwhen administered to a patient, known or suspected of being particularlysusceptible to a disease, in a prophylactically effective amount, has aprophylactic beneficial effect on the health and well-being of thepatient. A prophylactic beneficial effect on the health and well-beingof a patient includes, but is not limited to: (1) preventing or delayingon-set of the disease or condition in the first place; (2) maintaining adisease or condition at a retrogressed level once such level has beenachieved by a therapeutically effective amount of a substance, which maybe the same as or different from the substance used in aprophylactically effective amount; or, (3) preventing or delayingrecurrence of the disease or condition after a course of treatment witha therapeutically effective amount of a substance, which may be the sameas or different from the substance used in a prophylactically effectiveamount, has concluded.

As used herein, “therapeutic agent” also refers to pharmaceuticallyacceptable, pharmacologically active derivatives of those agentsspecifically mentioned herein, including, but not limited to, salts,esters, amides, and the like. Substances useful for diagnostics are alsoencompassed by the term “therapeutic agent” as used herein.

As used herein, the terms “therapeutic agent,” “drug,” “bioactiveagent”, “biologically active agent,” “biological agent,” and “activeingredient,” will be used interchangeably.

A “pharmaceutical formulation” may be a therapeutic agent in combinationwith a pharmaceutical excipient. A pharmaceutical formulation may be asolid, semi-solid, a gel, a liquid, a suspension, a powder, or anotherphysical form. As used herein, a “pharmaceutical formulation”encompasses a therapeutic agent in combination with an excipient that isloaded into the lumen of a structural element of a stent, and which isintended to remain within the lumen of the structural element of thestent until implanted into a patient.

As used herein, an “excipient” may be a substance that is combined witha therapeutic agent to form a final dosage form. Excipients arenon-toxic, and are typically inert, that is the excipient itself is nota therapeutic agent. Excipients typically perform a function such asacting as a binder for the therapeutic agent, a carrier or a diluent forthe therapeutic agent, a permeation enhancer, or an antioxidant orstabilizer for the therapeutic agent. In some cases vitamins and/orminerals, which may have therapeutic uses themselves, may also be anexcipient. One of skill in the art can readily determine if a vitamin ormineral is being used as an excipient in a pharmaceutical formulation,and/or if the vitamin or mineral is a therapeutic agent in thepharmaceutical formulation. Unlike a solvent which is removed from thefinal dosage form, an excipient is not removed, but remains part of thefinal dosage form.

As used herein, a “solvent” can be as a substance capable of dissolving,partially dissolving, dispersing, or suspending one or more substancesto form a uniform dispersion and/or solution, with or without agitation,at a selected temperature and pressure, and which is not an excipient.The substance may be a liquid, a gas, or a supercritical fluid. Asolvent herein may be a blend of two or more such substances. As usedherein, a substance used as an excipient in a pharmaceutical formulationis not a solvent even if it is capable of dissolving, partiallydissolving, dispersing, or suspending one or more substances to form auniform dispersion and/or solution. As used herein, a solvent may beused as a processing aid in forming a pharmaceutical formulation, but isremoved, or substantially removed, during processing and does not formpart of the final pharmaceutical formulation (except for incidentalresidual solvent).

A “fluid,” as defined by Merriam Webster dictionary, is a substance thattends to flow or conform to the outline of it's container. A fluid is astate of matter that includes gases, liquids, supercritical fluids, andplasma. As used herein, a fluid can be a substance having a viscosity asmeasured under the temperature and pressure of interest of 10,000 cP orlower. As used herein, a fluid can be a substance that would conform tothe shape of its container within a time frame of minutes (up to anhour) under the force of gravity.

A solid is one of the three states of matter—gas, liquid, and solid. A“solid” as defined by the Merriam Webster dictionary, is a substancethat does not flow perceptibly under moderate stress, has “a definitecapacity for resisting forces” such as compression or tension “whichtend to deform it,” and “under ordinary conditions retains a definiteshape and size.” As used herein, a “solid” can be a substance ofdefinite shape and size and that does not conform to the outline of it'scontainer under the force of gravity. As used herein, a solid may be asubstance that conforms to the outline of its container by breakingchemical bonds, requires extensive deformation as with a metal, or, ifan elastic solid, a substance that conforms with the application ofstress, but returns to its prior shape, or substantially its priorshape, when the stress is removed. A substance may be defined to be asolid at a specified temperature and pressure if it has a “viscosity” ofgreater than 10¹² cP at that specified temperature and pressure.

A “semi-solid” as defined by Merriam Webster dictionary is “a substancehaving qualities of both a solid and a liquid; highly viscous.” As usedherein, a substance can be a “semi-solid” at a specific temperature andpressure if it is a fluid having a viscosity greater than 10,000 cP. Asused herein, a semi-solid can be a substance that would conform to theshape of its container under high stress and/or over a long period oftime (months or years).

As used herein, a “particle” may be a piece of matter of any shape heldtogether by physical bonding of molecules, held together by chemicalbonds, such as a cross-linked polymer network, held together by ionicinteractions, an agglomeration of particles held together by colloidalforces and/or surface forces, or a piece of matter held together by anycombination of agglomeration, surface forces, colloidal forces, ionicinteractions, and chemical bonds. For the purposes of this disclosure, aparticle may be defined as ranging in size from less than one tenth of ananometer up to several centimeters in size. In addition, a particle mayinclude one or more types of constituent molecules.

For a plurality of particles, the “average” diameter may be anumber-average diameter, a surface area diameter, or a volume averagediameter as the particles are typically not all the same size and shape.The determination of any of these diameters typically involvesapproximating the diameter of an individual particle as a sphere of thesame surface area, same volume, etc. Dynamic light scattering or PhotoCorrelation Spectroscopy is often used to determine particle sizedistributions, and it determines a “Z average” diameter which is closeto the volume average diameter. The methods of determining the sizedistribution of a plurality of particles and the average diameterthereof are known in the art.

The polydispersity of a plurality of particles is a measure of thenarrowness or broadness of the distribution of the particle sizes aroundthe average. The standard deviation, which is a well-known statisticalmeasurement, may be suitable for a narrow particle size distribution.The average may be referred to as a d50. Other measures ofpolydispersity include the d10, and d90 which refer to the diametersrepresenting the threshold where 10% of the distribution falls below thed10, and 90% of the distribution falls below the d90, respectively. Asan example, if the distribution is a distribution by number, at the d50,half or 50% of the number of particles have a diameter less than thed50. For an area average diameter, the d50 represents the diameter wherehalf the surface area represented by the plurality of particles is belowthe d50, and half the surface area represented by the plurality is abovethe d50. Likewise, for a mass or volume distribution, 50% of the mass orvolume is below the d50, and 50% of the mass or volume represented bythe plurality of particles is above the d50.

Aspects of the present invention are directed to methods of loading orfilling the lumen of a structural element of a stent. These are notmethods for filling a lumen of a structural element of a stent once thestent is implanted, that is the in vivo filling of the lumen of astructural element, but are methods used prior to packaging the stent,and prior to implantation of the stent. These methods could be usedbefore, or after, the stent is crimped onto the delivery catheter. Asnoted previously, a stent can be any device used to hold tissue in placein a patient's body. A stent can be a tubular shaped device formed of ascaffolding of a plurality of interconnecting structural elements, orstruts. Other variations of stents include coiled or helical stents, andfibers or filaments forming the structural elements of the stent. It isthe scaffolding that provides support or outward radial force to supporttissue, such as a vessel wall, when implanted. The pattern of thescaffolding, or stent pattern, can be designed so that the stent can beradially compressed (crimped) and radially expanded (to allowdeployment). The cross-section of the stent and/or the structuralelements forming the stent is not limited to a circle, but may beelliptical or some other cross-section. Typical stent dimensions for anexpanded coronary stent can be 2 to 5 mm in diameter, and 6 to 50 mm inlength. Typical dimensions for an expanded peripheral stent are 3 to 8mm in diameter, 8 mm to 20 mm in length, and about 80 microns to 250microns in thickness. Aspects of the present invention are directed tostents in which at least some of the structural elements, which may bestruts, have a lumen, or in other words, the struts can be, for example,essentially hollow cylinders.

Referring now in more detail to the exemplary drawings for purposes ofillustrating embodiments of the invention, wherein like referencenumerals designate corresponding or like elements among the severalviews, there is shown in FIG. 1A an exemplary stent 50 comprising aplurality of interconnected stent struts 52 configured to move relativeto each other. The stent struts 52 can be, for example, arranged in asinusoidal or serpentine pattern. The stent struts 52 can form aplurality of circumferential rings 54 that may be arranged axially toform a tubular scaffold configured to support biological tissue afterimplantation of the stent. The rings may be connected by as few as onelinking strut per ring, but two, three, or more be present, or many moreas depicted in FIG. 1. Surfaces of the tubular scaffold that faceradially inward are referred to collectively as the luminal surface ofthe stent. Surfaces of the tubular scaffold that face radially outwardare referred to collectively as the abluminal surface of the stent. Theabluminal surface is a tissue contacting surface for a stent used in ablood vessel. In some embodiments, the structural elements forming thescaffold have sidewall surfaces that connect the abluminal and luminalsurfaces. The “outer surface” of a stent may be any surface that wouldbe in contact with tissue or blood when implanted in a patient andtherefore includes abluminal and luminal surfaces and if present,sidewall surfaces. The pattern shown in FIG. 1A is an exemplaryembodiment, and the embodiments of the invention are not limited to whathas been illustrated as other stent patterns are easily applicable.Specifically, a stent which is a helix and/or coil is an alternativeconfiguration. The stent may be comprised of individual ring sections,or made of one length of wire.

The rings 54 can be configured to be collapsed to a smaller diameter,thereby allowing the stent to be crimped onto a balloon or other devicefor delivering the stent to the desired implantation site within apatent. The rings 54 can be also configured to expand when inside thepatient. The rings 54 can be expanded by inflation of a balloon on whichthe stent has been crimped, or alternatively, the rings can self-expandlike a spring upon removal of an outer sheath.

Each strut 52 and ring 54 may be, for example, made of a continuous tubeof material, a cross section of which is shown in FIG. 1B. The struts 52formed from the continuous tube are referred to herein as “strut tubes.”These strut tubes are exemplary, but not limiting, structural elementsof a stent. Although the exemplary stent is shown with a struts have acircular or essentially circular cross-section, the cross-section ofstruts or structural elements is not limited to these, and may beelliptical, polygonal, rectangular, etc. The tube stock used to make thestruts can be made from an extrusion process or other processes known inthe art for making tube stock. Although the precise dimensions of thetube stock may vary depending upon the intended use of the stent,suitable tube stock diameters and wall thicknesses for coronary use maybe between 40 and 200 microns and 10 to 80 microns, respectively. Thetube stock is essentially uniform in diameter and cross-section over itslength, but in some embodiments, the diameter and internal cross-sectionmay vary or fluctuate over the length of the tube. To make the stent,the tube stock may be bent into the serpentine pattern, then wrappedaround circumferentially to form the ring. Thus, bending may result in achange both the shape of the cross section as well as the internalcross-sectional area. A plurality of the rings can be made from asingle, continuous tube. Alternatively, each ring can be made from itstube, and the rings can be connected by welding or bonding the tubestogether or by attaching links to adjacent rings. In either case, therecan be openings at one or both ends of the tube providing access to thelumen. In some embodiments, one opening at the end of the tube may besealed, or plugged.

In the discussion that follows a reference to a strut tube or astructural element for use in a method or use with an apparatus or thelike is not so limited and embodiments of the invention also encompassthe use of a stent instead. Likewise, methods and apparatus that referto a stent in the description are not so limited and embodiments of theinvention also encompass the use of the strut tubes or structuralelements instead of the stent. As an example, and without limitation,the disclosure of immersing a structural element having a lumen into amaterial encompasses both immersion of an individual ring or strut tubeinto the material as well as the immersion of an entire stent having astrut tube.

A plurality of holes and/or pores, referred to hereinafter as sideopenings 56, exist in the strut tubes. In one aspect of the invention,the side openings may be pores and may not include holes formed atpredetermined locations. In another aspect of the invention, the sideopenings may be holes formed at pre-determined locations and not includeany pores. In still another aspect, the side openings may be acombination of pores and holes formed at pre-determined locations. Eachside opening 56 accesses the lumen of the strut tube 52 so that anycomposition 58 carried inside the lumen can escape out of the openingsafter the stent is implanted (as depicted by arrows in FIG. 1B). Thecomposition may include a therapeutic agent. One or more of the sideopenings are in fluid communication with each other through the internallumen. Although the side openings are illustrated as essentiallycircular in cross-section, the cross-section is not so limited and theopenings may be of any shape or any combination of shapes, such as,without limitation, elliptical, rectangular, circular, or polygonal. Theside openings extend from the internal surface or luminal surface of thestrut tube to the exterior surface of the strut tube. The side openingsmay be in the abluminal, luminal, and/or sidewall surfaces of the strut.The side opening may be in the form of a channel with a uniform orsubstantially uniform cross-section, or the cross-section may vary. Theaspect ratio of the opening may be 1, from 1 to 10, or in some casesgreater than 10. The aspect ratio is the width to height of an object,or more generally, the ratio of longest dimension and the shortestdimension of an object.

The side openings may be of a diameter that is significantly smallerthan that of the openings at the ends of the tube if end openings arepresent. In some embodiments, the size of an individual side opening, asdetermined by the area of the side opening on the internal surface ofthe tube is not more than 50% of the cross-sectional area of the openingat the end of the tube. As used herein “not more than 50% of thecross-sectional area of the opening at the end of the tube” means thesmaller of the areas if the two end openings are present and do not havethe same cross-sectional opening area. In an aspect of the presentinvention, this ratio is not more than 25%, and in still another aspectof the invention, not more than 10%. In another aspect of the invention,this ratio is not more than 5%. The side openings may be distributedalong the length of each structural element. There may be about 4 to 144side openings per ring. The distance between the side openings may beuniform or non-uniform.

Polishing and cleaning can be performed after the side openings 56 areformed in order to remove debris, burs and/or sharp edges. The sideopenings 56 can be made before or after the stock tube is formed intothe struts and rings of the stent. Initially, the stock tubes are hollowand contain no material. After completion of the manufacturing process,the strut tubes 52 contain a composition 58 which may includetherapeutic agent and/or other substances, some of which it may bedesired to be released out from the stent after implantation. Thecomposition can be filled in before or after the stock tube is formedinto the struts and rings of the stent. The composition can be filled inbefore or after the side openings 56 are formed. Processes for tubebending, creating the side openings, polishing and cleaning may generateheat, involve the application of heat to the tube, or use corrosivechemicals. Therefore, when the composition to be filled into the tube isheat sensitive, prone to degradation when exposed to heat, orsusceptible to the chemicals used, it is preferred to load the tube withthe composition after the tube has been formed into the struts and ringsof the stent, after the side openings are formed, and after anypolishing.

The tubes, or the structural elements, used to form a stent aregenerally made from a biocompatible metal or metal alloy. Exemplarymetals and metal alloys include, without limitation, cobalt-chromiumalloys (e.g., ELGILOY™, Haynes alloy 25™, L605) stainless steel (316L),“MP35N,” “MP20N,” ELASTINITE™ (nitinol), tantalum, tantalum-basedalloys, nickel-titanium alloy, platinum, platinum-based alloys such as,e.g., platinum-iridium alloy, iridium, gold, magnesium, titanium,titanium-based alloys, zirconium-based alloys, or combinations thereof.The tube or structural elements may be made from a biostable polymer, abioabsorable polymer, or a combination of a biostable polymer and abioabsorbable polymer. The tubes may be made from other materials suchas ceramics, and/or glass. Any of the above materials may be used incombination.

As noted above, the lumen of the strut tube is intended to be filled, orloaded, with one or more substances, hereinafter a “composition.” Thusthe substance filling or loaded into the strut tube lumen and which areintended to remain there until the stent is implanted may be referred toas a composition, and may include a therapeutic agent, and/or othersubstances. There are a number of challenges in filling such a lumen ofa strut tube with a therapeutic agent. First, a reproducible quantity ofthe therapeutic agent must be placed within the lumen of the stent or astrut tube used in forming the scaffolding of the stent because thestent as a whole must contain a reproducible amount or dosage of atherapeutic agent. Second, uniform loading of the therapeutic agentsalong the length of the stent is preferred. Third, the process used toload or fill the lumen must be accomplished with no or minimal (not morethan 10%, preferably not more than 5%) degradation of the therapeuticagent. Fourth, the process must result in no or a reproducible quantityof therapeutic agent outside the stent, that is on the outer surface,that is luminal, abluminal, and/or sidewall surfaces of the stent.Finally, the pharmaceutical formulation of the therapeutic agent must beshelf-life stable. The pharmaceutical formulation must also be releasedin vivo in a reproducible manner.

One manner of loading the composition into the lumen of the strut tubemay be to inject the composition into the openings at the end of thestrut tube, whether the strut tube forms one or multiple rings.Alternatively, the composition may be injected into the plurality ofside openings instead of or in addition to injection into the one orboth openings at the ends of the tube. In one embodiment, thecomposition is only introduced through the side openings as there are noopenings at the ends of the tube. In a preferred embodiment, ifinjection is used, the composition may be injected into one or bothopenings at the end of the tube.

FIG. 2 shows an injector for injecting a material into a tube 100 eitherbefore or after the tube has been formed into struts and rings of thestent, before or after openings are formed into the tube, and before orafter cleaning and polishing of the tube. The material injected may be acomposition that is to be loaded into the lumen. Alternatively, thematerial injected may be a composition that has been dispersed in and/ordissolved in a solvent to form a solution that is injected leaving thecomposition in the lumen of the strut tube after removal of the solvent.The injector is a syringe 102 with a reservoir 104 containing thematerial. There is a piston or plunger 106 and a hypotube 108 atopposite ends of the reservoir. A discharge opening 110 of the hypotubeis coupled to an inlet opening 112 at an end of the tube 100. A coupling111 connects the discharge opening 110 and the inlet opening 112together. Inward, axial movement of the plunger 106 causes the materialin the reservoir 104 to be pushed out of the hypotube 108 and into thetube 100. The plunger 106 can be manually operated by a person or can beattached to a motor or other device to allow for precise control ofmovement and pressure. It will be appreciated that a variety of othertypes of injectors may be used to fill the tube instead of the syringe102, including without limitation, a circumferential-piston pump, adiaphragm pump, a centrifugal pump, and a peristaltic pump.

An injector can be coupled to a tube in a number of ways, as shown inFIGS. 3A-3D. In FIG. 3A, a discharge opening 110 of an injector 102 isdisposed at the bottom of a counterbore 120 formed into the tip of theinjector. In this embodiment, the counterbore 120 functions as acoupling between the discharge opening 110 and the tube 100. Thecounterbore 120 is a cylindrical, flat-bottomed hole which enlarges thedischarge opening 110. The cylindrical walls of the counterbore 120 aresized to have an inner diameter 122 that is substantially the same as orslightly smaller than an outer diameter 124 of the tube 100. When thetube 100 is inserted into the counterbore 120, the cylindrical wallsprovide a tight, friction fit or compress the tube 100 to preventleakage of the material being injected into the tube.

In FIG. 3B, an inner diameter 122 of cylindrical walls of a counterbore120 are much greater than an outer diameter 124 of a tube 100. Anannular gasket 126 made of elastic material is inserted into thecounterbore 120. In this embodiment, the gasket 126 functions as acoupling between the discharge opening 110 and the tube 100. Athrough-hole 128 at the center of the gasket 126 is sized to have aninner diameter 130 that is slightly smaller than the outer diameter 124of the tube 100. When the tube 110 is inserted into the through-hole128, the gasket 126 deforms and forms a fluid-tight seal around the tube110. Various gaskets having different sized through-holes can be used toallow the injector 102 to be used to fill tubes of varying diameters.

In FIG. 3C, an injector 102 has a discharge opening 110 surrounded by anannular flange 132 on which a flat, circular membrane or gasket 134 isattached by a round cap 136. In this embodiment, the gasket 134functions as a coupling between the discharge opening 110 and the tube100. The cap 136 has a central hole 138 that exposes a surface 140 ofthe gasket 134. The central hole 138 is sized larger in diameter thanthe tube 100 to allow the injector to be used to fill other tubes withdifferent diameters. The exposed surface 140 of the gasket 134 initiallyhas no hole. The gasket 134 is made of an elastic material that can bepunctured by a tube 100. When the tube 100 is pushed through the gasket134, the opening 112 of the tube is disposed inside the dischargeopening 110 of the injector 102, and the gasket 134 forms a fluid-tightseal around the tube 110. The end of the tube can be cut at a bias orangle so as to produce a sharp point for piercing into the gasket 134.When the tube 100 is pulled out of the gasket 134, the gasket 134self-seals the hole left behind by the tube 100, thereby preventingspillage of the material inside the discharge opening 110.

In FIG. 3D, an elastic coupling sleeve 142 connects an ejector 102 to atube 100. The elastic coupling sleeve 142 has a first opening at a firstend 144 of the sleeve and a second opening at a second end 146 of thesleeve. The first opening at the first end 144 has an inner diameterthat is smaller than the outer diameter of the injector tip so that whenthe injector tip is inserted into the first opening, as shown in FIG.3D, the first end 144 is sealed tightly around the discharge opening 110of the injector 102. The second opening at the second end 146 has aninner diameter that is smaller than the outer diameter of the tube tipso that when the tube tip is inserted into the second opening, as shownin FIG. 3D, the second end 146 is sealed tightly around the inletopening 112 of the tube 110.

The material that is injected may be in the form of a solid powder.Preferably, the material is a composition that is a fluid. In oneembodiment, the composition may be a therapeutic agent that has beenmelted, and is then injected into the strut tube while molten, andsubsequently solidifies within the tube. The therapeutic agent may beheated until it melts, and then injected into the inlet opening and/oranother opening to fill the lumen of the strut tube. As used herein, thephrases, “load the strut tube,” “load the lumen of the strut tube,”“fill the strut tube” and “fill the lumen of the strut tube,” encompassboth partially and completely filling the lumen of the strut tube.

Therapeutic agents that are stable, or reasonably stable, in the melt,and which possess characteristics such that when at a temperature ofabout 30° C. and a pressure of about one atmosphere, the therapeuticagents are solids or semi-solids may be used. Therapeutic agents thatare solid or semi-solid at a temperature of about 30° C. and a pressureof about one atmosphere may be solids or semi-solids at temperaturesbelow about 30° C. and at pressures above about one atmosphere. As usedherein, “reasonably stable,” refers to a therapeutic agent that may beinjected as a melt with not more than 5% degradation occurring duringthe process, preferably not more than 2%. Percent degradation refers toa decrease in the purity and/or content of the therapeutic agent. Insome embodiments, the therapeutic agent may be a solid or a semi-solidat 25° C. and at one atmosphere, but may be a fluid above 25° C. at oneatmosphere. In still other embodiments, the therapeutic agent is onewhich is a fluid with a viscosity of not less than 10 cP, preferably notless than 100 cP, more preferably not less than 1000 cP, and even morepreferably not less than 5000 cP, at about 30° C. and a pressure ofabout one atmosphere. Such fluids will have a higher viscosity attemperatures less than about 30° C. at about one atmosphere. Theviscosity of the composition that fills the lumen of the strut tubesthat can be utilized may be a function of the size of the side openingswith smaller side openings allowing for a lower viscosity fluid to beused as the composition. Examples of therapeutic agents which may bemelted and injected include, without limitation, paclitaxel, protaxel,dexamethasone, momentasone, clobetasol, and dexamethasone acetate. Acombination of therapeutic agents may be used in any of the embodimentsof the present invention.

If the therapeutic agent to be used is not reasonably stable whenmelted, then the composition may be a pharmaceutical formulationincorporating the therapeutic agent and a low melting excipient suchthat the pharmaceutical formulation can be injected into the struttubes. The low melting excipient may be melted and the therapeutic agentmay be dissolved or dispersed in the excipient to form a pharmaceuticalformulation. The pharmaceutical formulation may be then injected intothe strut tube. The viscosity of the Examples of therapeutic agents thatmay be used in the low melting excipient pharmaceutical formulationsinclude, without limitation, zotarolimus, everolimus, sirolimus,biolimus, deforolimus, novolimus, myolimus, temsirolimus, and anycombination thereof.

In some embodiments, a low melting excipient may be an excipient whichmelts at not more than 60° C. when at one atmosphere pressure. In otherembodiments, a low melting excipient may be one which melts at not morethan 55° C. when at one atmosphere pressure. In still other embodiments,a low melting excipient may be one which melts a temperature of not morethan 50° C., a temperature of not more than 45° C., or a temperature ofnot more than 40° C. when at one atmosphere pressure. The excipient maybe chosen such that the when used in the appropriate amount in the finalpharmaceutical formulation the result is a pharmaceutical formulationthat is a solid or semi-solid when the pharmaceutical formulation is atabout one atmosphere pressure and at 30° C., and the pharmaceuticalformulation is also a solid or semi-solid at temperatures lower than 30°C. at a pressure of about one atmosphere. Therefore, the lower limit onthe melting temperature may be about 30° C., and preferably about 35° C.In some embodiments, the low melting excipient has a melting temperatureof above body temperature, about 37° C. for a human, and in someembodiments, the low melting excipient has a melting temperature ofabout body temperature.

Excipients chosen for use in a composition that to be loaded into thelumen of a strut tube and is a pharmaceutical formulation with a lowmelting excipient previously described as well as those pharmaceuticalformulations to be described subsequently, may be biocompatible,compatible with the therapeutic agent, and shelf-life stable incombination with the therapeutic agent.

Examples of low melting excipients include, without limitation, solidpoloxamers, TWEEN™ 60 (polysorbate 60), Vitamin E TGPS, PLURONIC® F68,PLURONIC® F127, Poloxamer 407, ascorbyl palmitate, lecithin, egg yolkphospholipid, phosphatidylcholine, polyethylene glycol-phosphatidylethanolamine conjugate (PEG-PE), polyethylene glycol, triglycerides,diglycerides, monoglycerides, fatty alcohols such as aliphatic alcoholshaving a chain of 8 to 22 carbon atoms, and any combination thereof.Vitamin E TPGS is also known as D-alpha tocopheryl polyethylene glycol1000 succinate, and is a water soluble form of Vitamin E. Aspecification for Vitamin-E TPGS is listed in the United States NationalFormulary (NF). Polysorbates are a group of oleate esters of sorbitoland its' anhydrides condensed with polymers of ethylene oxide.Polysorbates are used as emulsifiers and surfactants in food,pharmaceuticals and cosmetics. Examples include polysorbate 20,polysorbate 60, and polysorbate 80, the specifications of which are alllisted in the United States Pharmacopeia (USP). PLURONIC® is a tradename of BASF and encompasses a group of block copolymers formed fromethylene oxide and propylene oxide. Poloxamers are copolymers with acentral block of polypropylene oxide) (PPO) and with a block ofpoly(ethylene oxide) (PEO) on each side where the PEO blocks are usuallyof the same length as determined by the number of constitutional units.Poloxamers of types 124, 188, 237, 338, and 407 are specified by amonograph in the National Formulary. Many of the PLURONIC® polymers aresurfactants, and some of them also comply with one of the NF monographsfor Poloxamers.

Excipients used in a composition to be loaded into the lumen of a struttube including the composition which is a pharmaceutical formulationwith a low melting excipient described above and all of the compositionsto be described subsequently, may be chosen to facilitate release of thetherapeutic agent from the strut tube after implantation in a patient.In some embodiments, an excipient may be chosen to increase thedissolution and/or release rate of a therapeutic agent, or to decreasethe dissolution and/or release rate of a therapeutic agent. For exampleand without limitation, the excipient PFE-PE would be expected toincrease the dissolution of a hydrophobic drug. As another example,without limitation, the triglyceride glycerol-tristearate would beexpected to decrease the dissolution of hydrophilic drug.

A sustained release of a therapeutic agent over time may be when notmore than 80% of the drug is released in the first 12 hours postimplantation, 24 hours post implantation, 36 hours post implantation, orfirst week post implantation. In some embodiments, sustained release ofa therapeutic agent over time may be 80% of the drug will have beenreleased in a time frame ranging from 24 hours post implantation to 72hours post implantation.

The pharmaceutical formulation with a low melting excipient may includebetween about 2 weight % (wt %) and about 90 wt %, preferably betweenabout 5 wt % and about 50 wt %, and even more preferably 10 wt % and 35wt % therapeutic agent. The pharmaceutical formulation may include otherexcipients in addition to the low melting excipient such as, withoutlimitation, stabilizers, anti-oxidants, lubricants, carriers, and/ordiluents.

In some embodiments, even if the therapeutic agent is reasonably stablein the melt, the composition that is loaded into the lumen of a struttube may be the therapeutic agent combined with an excipient to form apharmaceutical formulation. If the therapeutic agent is one which isreasonably stable in the melt, the excipients added may function as adiluent to control the dose, facilitate dissolution, or retarddissolution. Other types of excipients that may be used include thosetypes that are typically used in pharmaceutical formulations. Examplesinclude, without limitation, stabilizers, anti-oxidants, lubricants,and/or carriers. Thus, in some embodiments including a reasonably stabletherapeutic agent, the composition injected will be about 98 wt %, about99 wt %, or about 100 wt % therapeutic agent, or will consistessentially of the therapeutic agent. In other embodiments, thecomposition may be a pharmaceutical formulation that is to be injected,the pharmaceutical formulation may include between about 50 wt % and 99wt % therapeutic agent, preferably between 60 wt % and 98 wt %therapeutic agent, and more preferably between 65 wt % and 95 wt %therapeutic agent. It is understood that therapeutic agents “asreceived,” or as used or as added to a pharmaceutical formulation, donot assay at 100% therapeutic agent, but may contain up to about 5%incidental impurities or other substances.

During the injection, and optionally for some time after the completionof the injection, the stent, or strut tube, and the composition withinthe lumen and/or within the injector may be maintained at a temperature,or within a temperature range, sufficient to maintain the composition ina fluid state. The temperature may fluctuate or change provided that thecomposition remains in a fluid state. In some embodiments, the stent orstrut tube may be maintained at and/or above a specific temperatureduring the injection, and optionally for some period of time after theinjection, where the specific temperature may be 30° C., 35° C., 40° C.,or 45° C. In other embodiments, the specific temperature may be themelting temperature of the therapeutic agent, the melting temperature ofthe pharmaceutical formulation, or the melting temperature of theexcipient, or higher, and in still other embodiments, the specifictemperature may be 5° C., 10° C., or 15° C. higher than the meltingtemperature of the therapeutic agent, the pharmaceutical formulation, orthe excipient. During the operation of melting the therapeutic agent ordissolving and/or dispersing the therapeutic agent in the moltenexcipient, as well as during the injection of the composition which maybe a therapeutic agent or pharmaceutical formulation thereof, thetemperature may not exceed a temperature, which may be referred to as amaximum temperature, at which significant degradation of the therapeuticagent may occur during the time period of the melting ordissolving/dispersing operation, and the injection operation. As usedherein, “significant degradation” will be degradation of more than 5%.In some embodiments, a maximum temperature may be selected such that thedegradation of the therapeutic agent is not more than 3%, and in stillother embodiments, not more than 1%. Various embodiments of theinvention encompass a maximum temperature of 60° C., 65° C., 70° C., and80° C.

In some embodiments, the stent or strut tube and the composition withinthe lumen and/or injector may be maintained at a temperature, or withina temperature range, sufficient to maintain the composition in a fluidstate with a viscosity of not more than 10,000 cP, preferably not morethan 5000 cP, and even more preferably, not more than 100 cP during theinjection. In still other embodiments, the, the stent or strut tube andthe composition within the lumen and/or injector may be maintained at atemperature, or within a temperature range, sufficient to maintain thecomposition in a fluid state with a viscosity in the range of about 5 cPto about 10,000 cP, but preferably in the range of 5 cP to about 100 cP.The viscosity may be determined using a capillary rheometer, cone andplate viscometer, capillary viscometer, cuette viscometer, or fallingball viscometer. The fluid may be Newtonian or non-Newtonian. Forexcipients which are macromolecules, shear thinning behavior may beadvantageous. In the case of non-Newtonian fluids, measuring the low orzero shear viscosity is the value most predictive of the fluid behaviorduring injection or loading as this will be a low flow rate process.Maintaining the strut tube and/or the injector containing thetherapeutic agent or pharmaceutical formulation thereof at or within aspecified temperature range may be accomplished by methods that arewell-known in the art such as use of a heating jacket or coils, aninfrared lamp, blow dryer, etc.

The injection of the composition, whether the composition is a moltentherapeutic agent or the pharmaceutical formulation including atherapeutic agent in any of the embodiments described above, uses apressure in the range of 10 to 15,000 lb/in². Other embodimentsencompass a pressure in the range of 10 to 5,000 lb/in², 100 to 10,000lb/in², 10,000 to 15,000 lb/in², or 12,000 to 15,000 lb/in².

In some embodiments, the injection may occur in an inert atmosphere,that is one free of oxygen or substantially free of oxygen (such as, forexample and without limitation, <1000 ppm oxygen). In some embodiments,the injection occurs in an environment that is free of or substantiallyfree of humidity (not more than 5% rh), or an environment of lowhumidity (between about 5% and not more than 20% rh).

In some embodiments, the injection may end when the composition isvisible at the other inlet opening of the strut tube if present and ifopen. In some embodiments, the injection may end when a specified weightor volume of the composition has been added to the strut tube.

After the injection, the composition may be allowed to cool to roomtemperature, that is approximately 20° C. to 25° C. and one atmosphere.After cooling the composition, that is the therapeutic agent orpharmaceutical formulation thereof, is a solid or a semi-solid. In someembodiments, the semi-solid has a viscosity of not less than 15,000 cP,while in other embodiments, the viscosity may be not less than 10,000cP. In still other embodiments, after cooling to room temperature, thecomposition is a fluid having a viscosity not less than 10 cp,preferably not less 100 cP, more preferably not less than 500 cP, evenmore preferably not less than 1000 cP, and still even more preferably,not less than 5000 cP. The rate of decrease in the temperature of thestent or strut tube filled with the composition may be increased by theuse of a fan, placement of the filled strut tube in an environment withan ambient temperature below 25° C., or use of a cooling coil whichsurrounds the strut tube and has a fluid flowing through the coil, thefluid being at a temperature below 25° C. Other methods of increasingthe cooling rate include contact with an object of high thermalconductivity which is at a lower temperature, immersion of the filledstent in a fluid of a temperature lower than that of the stent, andimmersion in an ice bath or other cooling bath. As used herein, thephrases, “cooling the strut tube” and “cooling the stent,” willencompass both passive cooling, that is removing any source of heat, andallowing the stent to cool in the ambient surroundings without makingany other changes to the surroundings, and active cooling, whichincludes, in addition to the removal of a heat source, taking one ormore active measures to increase the rate of cooling, such as, forexample and without limitation, using a fan, or another measureincluding, but not limited to, those described above.

The advantage of using a therapeutic agent in the melt, or apharmaceutical formulation of a therapeutic agent in a molten or fluidstate, is that the use of a solvent as a carrier is avoided. Thus, forthe methods described above, the composition injected, whether atherapeutic agent alone or a pharmaceutical formulation thereof, is freeof, or essentially free of, solvents. All of the composition that isinjected remains, or essentially remains, inside the lumen of the struttube. Residual solvent inside the strut tube may lead to stabilityissues for the therapeutic agent. The therapeutic agent may be degradedwith time or the solvent content inside the strut tube may change withtime which can lead to a change in the agent release rate. It is alsoundesirable to release solvents in vivo due to biocompatibility ortoxicity issues.

In some embodiments, the internal lumen of the strut tube may be coatedwith or exposed to a lubricant prior to the injection. Examples oflubricants include, without limitation, silicone oil and varioussilicone fluids, liquid PEG, liquid mono-, di- and triglycerides,vegetable oils, glycerol propylene glycol, magnesium stearate, calciumstearate, zinc stearate, stearic acid, talc, and starch. The lubricantmay be dissolved in a solvent or fluidized or atomized in air, anothergas, or a fluid, which may be blown through the strut tube, or ifpresent as liquid or fluid, may be injected into the strut tube, todeposit the lubricant onto the luminal surface of the strut tube. If asolvent is used, the solvent may be evaporated.

In another embodiment, the composition which may be a therapeutic agentor a pharmaceutical formulation thereof, may be dissolved or dispersedin, but preferably dissolved in, a solvent to form an injectionsolution. The injection solution may be injected into the lumen of thestrut tube, and then the solvent may be removed leaving the compositionin the lumen. Injection may be into one or both end openings, ifpresent, and/or one or more side openings. Due to the small diameter ofthe lumen of the strut tube as well as the small size of the sideopenings about the surface thereof, the removal of the solvent may bedifficult. Thus, the methods preferably use solvents that are in a gasphase at about 20° C. to 25° C. and one atmosphere, and therefore,readily evaporate.

The methods using an injection solution may involve changing thecondition of temperature and/or pressure such that the injectionsolution is in a liquid or supercritical fluid state. The method mayinclude a decrease in the temperature and/or an increase in the pressuresuch that the solvent and/or the injection solution is in a liquid orsupercritical state. The injection solution may be then injected intothe lumen of the strut tube under a condition of temperature andpressure that maintain the injection solution in a liquid orsupercritical fluid state. Similar to the situation describedpreviously, “maintain the temperature and pressure” allows forfluctuations in the temperature and pressure provided that the injectionsolution remains in a supercritical or liquid state. In someembodiments, the temperature and pressure may be maintained within arange such that density fluctuations of the injection solution are notmore than 5%. Once the injection has been completed, the condition oftemperature and pressure of the filled strut tube may be changed suchthat the strut tube and its contents are at about 20° C. to 25° C. andone atmosphere. At this temperature and pressure, the solvent is a gas,and the solvent will boil and dissipate through the side openings and/orthe openings at the ends of the tube, leaving behind, or substantiallyleaving behind, in the lumen of the strut tube, the composition which isa therapeutic agent or a pharmaceutical formulation thereof. Because thesolvent occupies some volume, more than one cycle of injecting aninjection solution followed by a change in the condition of the struttube and its contents may be required to fill the lumen with the desiredquantity of the composition. Therefore, the cycle may be repeated one ormore additional times. For example two cycles, three cycles, or morethan three cycles may be performed.

One class of substances that may be used as solvents are thosesubstances having a boiling point below room temperature, that is belowabout 20° C. to 25° C. at a pressure of one atmosphere. In someembodiments the solvent has a boiling point, measured at a pressure ofone atmosphere, below 20° C., preferably below 10° C., more preferablybelow 0° C., and even more preferably below −10° C. Some examples ofsubstances that may be used as solvents include, without limitation,propane, pentane, cyclopentane, butane, dimethylether, trifluoromethane,dichlorodifluoromethane, chlorodifluoromethane,1,2-dichloro-1,1,2,2-tetrafluoroethane, 1-chloro-1,1-difluoroethane,FREON® solvents where FREON® is the trade name of DuPont for a number ofchlorofluorocarbons, chlorofluorohydrocarbons, fluorohydrocarbons, andhalons. Halons are hydrocarbons in which one or more hydrogen atoms arereplaced with bromine, and other hydrogen atoms with other halogen atoms(fluorine, chlorine, and iodine). FREON® solvents include, HFC134a™, thetrade name for 1,1,1,2-tetrafluoroethane (CF₃CFH₂), and HFC-227EA™, thetrade name for 1,1,1,2,3,3,3-heptafluoropropane (CF₃CHFCF₃). HFC-134ahas a boiling point of −26° C. HFC-227ea has a boiling point of −16° C.Both HFC-134a and HFC-227ea are used as propellants for medicalaerosols. In some embodiments, supercritical carbon dioxide (CO₂) oranother supercritical fluid may be used. In still other embodimentsliquid CO₂ may be used.

The injection solution may be formed by either decreasing thetemperature, and/or increasing the pressure of the solvent such that itis in either a liquid or supercritical state, and then dissolving ordispersing the therapeutic agent, and optionally an excipient into thesolvent in this liquid or supercritical state to form the injectionsolution. In some embodiments, the solvent may be cooled to atemperature in the range of 20° C. to −60° C., for example and withoutlimitation, to at least 5° C., at least 0° C., at least −10° C., atleast −20° C., at least −30° C., at least −40° C., at least −50° C., orat least −60° C., while the pressure remains at about one atmosphere. Insome embodiments, the solvent pressure may be increased to about 2 toabout 32 atmospheres, for example and without limitation, at least 5atmospheres, at least 10 atmospheres, at least 20 atmospheres, or atleast 32.5 atmospheres. In still other embodiments, the addition of thetherapeutic agent and the optional excipient result in boiling pointelevation, or in other words, the injection solution thus formed has aboiling point that may be higher than that of the solvent alone.

The injection solution may include between 10 wt % and 99 wt % solvent,preferably between 20 wt % and 98 wt % solvent, and even more preferablybetween preferably 25 wt % and 95 wt % solvent. If the therapeutic agentis formulated with an excipient to form a pharmaceutical formulation,the therapeutic agent may be between 0.5 wt % and 99 wt % of thepharmaceutical formulation, preferably between 1 wt % and 98 wt %, andmore preferably between 5 wt % and 95 wt %. The solvent is not intendedto form part of the final pharmaceutical formulation even though someresidual solvent may remain.

In some embodiments, the injection solution may include an additive oran excipient that causes the solution to have a contact angle of lessthan 90 degrees on the surface of the structural element to allow thesolution to penetrate into the lumen with greater ease than if theadditive were not present. In some embodiments, the injection solutionmay include a wetting enhancement fluid which allows the solution tohave a contact angle of less than 90 degrees on the surface of thestructural element to allow the solution to penetrate into the lumenwith greater ease than if the wetting enhancement fluid was not present.An additive is another substance which may be added to the injectionsolution and/or to a composition which is not intended to remain in thelumen. In other words, it may be a solvent, or another substance, whichis not incorporated, or not intended to be incorporated, into thecomposition that fills the lumen (except for residual incidentalamounts). Similarly, a substance which causes the solution to have acontact angle of less than 90 degrees on the surface of a structuralelement to allow the solution to more easily penetrate the lumen that ifthe substance were not present but which substance is incorporated intothe composition remaining in the lumen is an excipient. A wetting fluidmay be a solvent, an additive, or an excipient. An additive may be asolvent. Examples of substances that may cause the solution to have acontact angle of less than 90 degrees include, but are not limited to,surfactants. Many surfactants are also excipients.

In some embodiments, the strut tube may be chilled to a temperature inthe range of about 20° C. to −60° C. prior to injection of the injectionsolution, for example and without limitation, to at least 5° C., atleast 0° C., at least −10° C., at least −20° C., at least −30° C., atleast −40° C., at least −50° C., or at least −60° C., while the pressureremains at about one atmosphere. In some embodiments, the stent may beplaced in an environment (e.g. pressure chamber) in which the pressureis increased to about 2 to about 100 atmospheres, for example andwithout limitation, at least 5 atmospheres, at least 10 atmospheres, atleast 20 atmospheres, at least 32.5 atmospheres, or at least 73atmospheres. In some embodiments, if there is more than one tube endopening, the other end opening may be plugged with a removable plug.Methods of plugging the end openings, and optionally side openings, arediscussed below.

During the injection, the condition of temperature and pressure may bemaintained such that the injection solution is in a liquid or asupercritical state. Thus, the temperature may be maintained to be notmore than a specific temperature in the range of about 40° C. to about−60° C., such as, without limitation, not more than 10° C., not more 0°C., not more than −10° C., not more than −20° C., not more than −40° C.,or not more than −60° C. The pressure may be at about 1 atmosphere ormuch higher than 1 atmosphere, such as between 72.9 and 100 atm. Thelower limit on the temperature during the injection and optionally forsome time subsequent thereto may depend upon the specific materials ofconstruction of the strut tube, the injector and connectors, as well asthe attributes of the composition, that is therapeutic agent and theoptional excipient. In some embodiments, the lower limit on thetemperature may be about −123° C. As an example and without limitation,the lower limit of the temperature may be one that would be below theglass transition temperature of material of a gasket, such as gasket 126or gasket 134 discussed above, or of a sleeve, such as elastic couplingsleeve 142 discussed above as below the glass transition temperaturethese materials would become hard and brittle. In some embodiments thepressure may be maintained such that it does not fall below 100atmospheres, below 73 atmospheres, below 32.5 atmospheres, below 20atmospheres, below 10 atmospheres, or below 2 atmospheres. Also, theupper limit of pressure will depend upon the specific materials ofconstruction of the stent and the dimensions of the strut tube, and theinjector and any other apparatuses used in the injection, as well as theattributes of the composition to be loaded and the solvent. The upperlimit on pressure may be about 50,000 lb/in².

The pressure required to effect the injection may be about 10 to about10,000 lb/in² in excess of the pressure required to maintain theinjection solution in a liquid or in a supercritical state. Theinjection solution may have a viscosity of not more than 10,000 cP butnot less than 1 cP under the temperature and pressure conditions of theinjection, but preferably the viscosity of the injection solution is notmore than 100 cP.

The injection may be executed in an inert and/or low humidityenvironment in the same manner as described above for the otherembodiments.

After the injection is complete, the condition of temperature andpressure may be changed such that the solvent boils and evaporates fromthe injection solution, leaving the therapeutic agent, or apharmaceutical formulation comprising the therapeutic agent and theoptional excipient, in the lumen of the strut tube. The evaporatingsolvent may incidentally carry with it some of the therapeutic agent andthe optional excipient. In some embodiments, 90 wt % or more of the sumof the weights of the therapeutic agent and optional excipient that areinjected into the strut tube lumen remain in the lumen after the solventevaporates, while in other embodiments 95% wt % or more remains or 98 wt% or more remains. The change in the temperature may occur as a resultof removing any coolant source, removing the strut tube and its contentsfrom a bath or a cool environment and then allowing the strut tube andits contents to warm to about approximately 20° C. to 25° C., or thestrut tube and its contents may be actively heated by known means untilthe temperature is approximately 20° C. to 25° C. In other embodiments,the strut tube and its contents are brought to a temperature of above25° C., such as at least 30° C. or at least 35° C. Similarly, thepressure condition may be changed by moving the strut tube and itscontents to a lower pressure environment or relieving a pressure valve,and then allowing the pressure to equilibrate to about one atmosphere.Alternatively, the pressure may be changed by pulling a vacuum. If thestrut tube and its contents are in a closed chamber, both thetemperature and pressure may be altered via a controller connected tothe necessary valves and sensors that allow the condition of pressureand temperature to be changed.

The change in the temperature and pressure may occur gradually over atime period of 5 to 60 minutes, or may occur essentially instantaneouslyin less than one minute. The change in condition may occur by increasingthe temperature followed by a decrease in pressure, or decreasing thepressure followed by an increase in temperature. In some embodiments,the temperature and pressure may change simultaneously, or may changesuch that there is some overlap in time between the time period overwhich the pressure change occurs and the time period over which thetemperature change occurs.

As discussed above, when the composition is loaded by injecting aninjection solution with subsequent evaporation of the solvent, more thanone cycle may be required. Each cycle may use an injection solution ofthe same composition, that is the same wt % of the therapeutic agent andoptional excipient. Alternatively, each cycle may use the sametherapeutic agent and optional excipient, but the composition may differin the wt % of the therapeutic agent and optional excipient. In yetanother alternative, the injection solution may differ because thesolvent is different, the therapeutic agent is different, and/or theoptional excipient is different. As used herein, a “differenttherapeutic agent” covers the situation in which the two agents onlydiffer because one is a salt, different salt, a hydrate, a differenthydrate, or a polymorph of the other, as well as the situation in thepharmacological activity of the two agents is the result of a differentchemical entity. With respect to the multiple injection cycles, theinjection solution in a cycle after the initial cycle may be near or atsaturation of the therapeutic agent and/or optional excipient to preventor limit the dissolution of the composition already deposited within thelumen during the injections after the initial injection.

In some cases, the lumen of the strut tube is not entirely filled withthe composition even after multiple cycles of injecting the injectionsolution.

The composition remaining in the lumen after one or more cycles ofinjecting an injection solution and changing the condition of pressureand temperature is the therapeutic agent or pharmaceutical formulationthereof, in a solid or a semi-solid form. In some embodiments, thesemi-solid has a viscosity of not less than 15,000 cP, while in otherembodiments, the viscosity may be not less than 10,000 cP. In stillother embodiments, the composition remaining in the lumen after thesolvent has evaporated is a fluid having a viscosity not less than 10cp, preferably not less 100 cP, more preferably not less than 500 cP,even more preferably not less than 1000 cP, and still even morepreferably, not less than 5000 cP. In some embodiments, the therapeuticagent is dispersed, either uniformly or non-uniformly, in the excipient.

In other embodiments, the material injected may be a composition that isa semi-solid or high viscosity fluid. The composition may be apharmaceutical formulation of a therapeutic agent and an excipient thatmay be non-volatile, and may possess characteristics such that it is asemi-solid or liquid at about 20° C. to about 30° C. and a pressure ofabout one atmosphere. The pharmaceutical formulation may have aviscosity of not more than 10,000 cP when the pharmaceutical formulationis at a temperature of about 20° C. to 30° C. and a pressure of aboutone atmosphere, and may be referred to as a “high viscositypharmaceutical formulation.” In some embodiments, the viscosity of thepharmaceutical formulation may be at least 10 cP or at least 100 cP, andin other embodiments, at least 1000 cP at a temperature of about 20° C.to 30° C. and a pressure of about one atmosphere. In still furtherembodiments, the pharmaceutical formulations may have a viscosity of atleast 5000 cP or at least 7500 cP at a temperature of about 20° C. to30° C. and a pressure of about one atmosphere. The viscosity of thepharmaceutical formulation may be high enough that the pharmaceuticalformulation does not leak, or flow, or essentially does not leak orflow, through the side openings and/or end openings in the strut tubeprior to the stent formed of such strut tubes being implanted. As aresult, the viscosity of the fluid may be decreased as the size of theside openings is decreased.

These embodiments differ from the other embodiments in that neither asolvent, nor heating, of the composition is required. Therefore, thecomposition injected, which is a high viscosity pharmaceuticalformulation, is free of, or essentially free of, solvents. Thepharmaceutical formulation may be in the form of a paste, a gel, or ahydrogel. A gel may be a semi-rigid material which is a colloidaldispersion of a solid in a liquid. For a hydrogel, the liquid is water.

The therapeutic agent may be formulated with a high viscosity,non-volatile (or essentially non-volatile) excipient such that theresulting pharmaceutical formulation has a viscosity of at least 10 cP.The excipients used may have a viscosity of at least 10 cP, butpreferably at least 100 cP, and more preferably at least 250 cP, at atemperature of about 20° C. to 30° C. and a pressure of about oneatmosphere. In some embodiments, the excipient has a viscosity of atleast 1000 cP or at least 5000 cP at a temperature of about 20° C. to30° C. and a pressure of about one atmosphere. In some embodiments, theexcipient is a semi-solid. In some embodiments, the excipients used mayhave a viscosity of slightly less than 100 cP, such as for example, atleast 85 cP, at a temperature of about 20° C. to 30° C. and a pressureof about one atmosphere, but when formulated the viscosity of thepharmaceutical formulation may be at least 100 cP.

The excipients chosen may be non-volatile, or essentially non-volatile.Non-volatile may be a vapor pressure of not more than 0.6 torr at 20° C.to 30° C. when measured at a pressure of about one atmosphere. In someembodiments, the excipient may have a vapor pressure of not more than0.06 torr at 20° C. to 30° C. when measured at a pressure of about oneatmosphere. In some embodiments, the excipient may lose not more than 3%of the initial weight when left in an open vial at USP controlled roomtemperature for 24 months, while in other embodiments the excipient maylose not more than 1.5% of its' initial weight.

Examples of excipients that may be used to form a high viscositypharmaceutical formulation include, without limitation, triglycerides,diglycerides, monoglycerides, soybean oil, safflower oil, peanut oil,vegetable oil, fatty alcohols, liquid poloxamers, TWEEN™ 20 (polysorbate20), TWEEN™ 80 (polysorbate 80), poly(ethylene glycol) of a numberaverage molecular weight of less than or equal to 1000 Daltons and/orabout 1000 Daltons, propylene glycol, glycerol, benzyl benzoate, benzylalcohol, dimethyl sulfoxide, N-methylpyrrolidone, and any combinationthereof.

The therapeutic agents used include, without limitation, any one or anycombination of those listed previously.

The therapeutic agent may be dissolved in the excipient, dispersed inthe excipient, or both dissolved and dispersed in the excipient. In someembodiments including the high viscosity formulation as well as thepharmaceutical formulations with a low melting excipient orpharmaceutical formulations using other excipients, the therapeuticagent may be in the form of and/or incorporated in microspheres,nanoparticles, microparticles, and/or microshells. A nano-particlerefers to a particle with a characteristic length (e.g., diameter) inthe range of about 1 nm to about 1,000 nm. A micro-particle refers to aparticle with a characteristic length in the range of greater than 1,000nm and less than about 10 micrometers. A plurality of particles ischaracterized by a distribution of particle size, and in someembodiments, the plurality of particles has an average diameter, asdetermined by dynamic light scattering, in the range of 0.1 nm to 1,000nm, or to about 1,000 nm, while in other embodiments, the plurality ofparticles has an average diameter greater than 1,000 nm and less than 10micrometers, or about 10 micrometers. The polydispersity of theplurality of particles, as measured by the ratio of the D90 to the D10of the particle size distribution determined by dynamic light scatteringmay be not more than 10, not more than 8, not more than 6, orpreferably, not more than 4.

Particles such as microspheres and nanoparticles typically include atherapeutic agent and another material. However, in some embodiments theparticles may be neat therapeutic agent, that is the particles may be,for example and without limitation, 100% or about 100% therapeuticagent, at least 99.0% therapeutic agent, at least 99.5% therapeuticagent, at least 99.8% therapeutic agent, or essentially 100% therapeuticagent. In other embodiments, the particles may have therapeutic agentsmixed, dispersed, and/or dissolved, and/or otherwise incorporated in theparticle material. The particle material can be biostable,biodegradable, or a combination thereof, and it may also be polymeric,metallic, ceramic, glass, or any combination thereof. In a preferredembodiment, the particles may include a polymer and a therapeutic agent,and may optionally an excipient.

Particles with therapeutic agent distributed throughout the particlematerial may be referred to as matrix type or monolithic type drugdelivery particles. The therapeutic agent may be homogeneously, orsubstantially homogeneously, distributed throughout the matrix ofparticle material, or the therapeutic agent distribution may benon-uniform. The particles can also encapsulate a therapeutic agenthaving an outer shell of material with an inner core containing thetherapeutic agent, and optionally another excipient. Such particles withan outer shell without therapeutic agent are typically referred to asreservoir type particles. In other embodiments, the therapeutic agentmay be included in an exterior coating or shell of the particlesurrounding a core. Particles may also be any combinations of the above.

The therapeutic agent may be included in a micelle, vesicle or liposomewhich may be dispersed in the excipient. A “micelle” refers to anaggregate (or cluster) of surfactant molecules. “Surfactants” refer tochemicals that are amphiphilic, which means that they contain bothhydrophobic and hydrophilic groups. Micelles tend to form when theconcentration of surfactant is greater than a critical micelleconcentration, and is essentially an aggregation of the moleculesessentially forming a sphere with the hydrophilic group of thesurfactant molecules forming a shell that contacts water around thehydrophobic groups in the core. Micelles may be formed from, forexample, block copolymers and/or lipids. Therapeutic agent may partitioninto the core or be incorporated within the micelle. A vesicle is arelatively small and enclosed compartment or shell formed by at leastone lipid bilayer. A lipid bilayer if formed from phospholipid moleculeshaving a hydrophilic head and a hydrophobic tail. Two layers ofmolecules form a shell in which the hydrophobic tails form the middle“layer” of the shell with the hydrophilic head groups facing theexterior of the vesicle and the interior aqueous compartment. In someembodiments, the exterior shell may be cross-linked to stabilize thevesicle or micelle.

The high viscosity pharmaceutical formulation may include thetherapeutic agent in the form of any type of particles listed above, orany combination of types of the particles listed above.

The high viscosity pharmaceutical formulation may include between 2 wt %and 90 wt %, about 2 wt %, or about 90 wt % therapeutic agent,preferably between 5 wt % and 50 wt %, about 5 wt %, or about 50 wt %therapeutic agent, or more preferably, between 10 wt % and 35 wt %,about 10 wt %, or about 35 wt % therapeutic agent whether thetherapeutic agent is dispersed in an excipient directly or in the formof a particle. If the pharmaceutical formulation includes microspheres,nanoparticles, microparticles, microshells, micelles, vesicles,liposomes and/or another type of particle (collectively “particles”),the weight percent of the pharmaceutical formulation that is particlesmay be between 2 wt % and 90 wt %, about 2 wt %, or about 90 wt %particles, preferably between 5 wt % and 50 wt %, about 5 wt %, or about50 wt % particles, or more preferably, between 10 wt % and 35 wt %,about 10 wt %, or about 35 wt % particles. The particles may be betweenabout 2 wt % and about 100%, or in some embodiments 100% therapeuticagent. If the particles include another material in addition to thetherapeutic agent, the particles may be between 5 wt % and 95 wt %therapeutic agent, about 5 wt %, or about 95 wt %, preferably between 20wt % and 95 wt %, about 20 wt %, or about 95 wt % therapeutic agent.

For the high viscosity pharmaceutical formulation, or any pharmaceuticalformulation that includes particles, whether the particles are ofessentially neat therapeutic agent, and/or the particles include aparticle material in addition to the therapeutic agent, the ratio of theinternal diameter of the lumen of the strut tube, or other structuralelement, to the average diameter of the particles may be not more than10, preferably not more than 12, more preferably not more than 15, andeven more preferably not more than 20. In some embodiments, the ratio ofthe internal diameter of the lumen of the structural element, such as astrut tube, to the D90 of the plurality of particles may be not morethan 10, preferably not more than 12, more preferably not more than 15,and even more preferably no more than 20. It is believed that use ofparticle diameters that are a larger fraction of the internal lumendiameter may result in poor flow of the pharmaceutical formulation,and/or uneven distribution of the therapeutic agent throughout thelumen.

The pharmaceutical formulation may include other excipients in additionto the high viscosity excipient such as, without limitation,stabilizers, anti-oxidants, lubricants, carriers, and/or diluents. Ifthe therapeutic agent is dispersed in the excipient and/or particlesincluding therapeutic agent are dispersed in the excipient, thepharmaceutical formulation may also include surfactants or dispersantsto minimize and/or prevent aggregation of the particles in thepharmaceutical formulation.

The injection of the high viscosity pharmaceutical formulation uses apressure in the range of 10 to 20,000 lb/in² gauge. Other embodimentsencompass a pressure in the range of 10 to 5,000 lb/in², 10 to 15,000lb/in², 10 to 10,000 lb/in², 100 to 10,000 lb/in², 10,000 to 15,000lb/in², 12,000 to 15,000 lb/in², or 15,000 to 20,000 lb/in². Unlessexpressly stated otherwise, all injection pressures refer to gaugepressure.

In some embodiments, the injection may occur in an inert atmosphereand/or in a low humidity atmosphere as described previously.

In some embodiments, the high viscosity pharmaceutical formulationutilizes some heating. The pharmaceutical formulation may be heated to aspecific temperature or to within a specific temperature range prior toinjection. In some embodiments, the specific temperature, or the lowerend of the specific temperature range to which the pharmaceuticalformulation is heated prior to injection, may be at, about, or at least28° C., 30° C., 35° C., or 40° C. The upper temperature of the range maybe at or about 30° C., 35° C., 40° C., or 45° C. Also, during theinjection and optionally for some time after the completion of theinjection, the strut tube, the injector, and the pharmaceuticalformulation within the lumen and/or within the injector may bemaintained at a specific temperature, and/or within a specifictemperature range which may be the same as or different from thespecific temperature or the specific temperature range to which thepharmaceutical formulation is heated prior to injection. In someembodiments, the specific temperature, or the lower end of the specifictemperature range at which the pharmaceutical formulation is maintainedduring the injection, may be at, about or at least 28° C., about or atleast 30° C., about or at least 35° C., or about or at least 40° C. Theupper temperature of the range may be at or about 30° C., at or about35° C., at or about 40° C., or at or about 45° C. The temperature mayfluctuate within a temperature range or around a specified temperature.

In some embodiments, the strut tube, the injector, and thepharmaceutical formulation within the lumen of the strut tube and/orinjector may be maintained at a temperature, or within a temperaturerange, sufficient to maintain the viscosity of the pharmaceuticalformulation of not more than 10,000 cP during the injection, preferablynot more than 5,000 cP during the injection, more preferably, not morethan 1,000 cP during the injection, and even more preferably, not morethan 100 cP.

For those embodiments utilizing heating of the high viscositypharmaceutical formulation, the temperature of the pharmaceuticalformulation may not exceed a temperature, which may be referred to as amaximum temperature, at which significant degradation of the therapeuticagent would occur during the time period of the heating prior to theinjection, during the injection, and optionally for some time periodafter the injection. In some embodiments, a maximum temperature may beselected such that the degradation of the therapeutic agent is not morethan 3%, and in still other embodiments, not more than 1% during thetime period of the heating prior to the injection, during the injection,and optionally for some time period after the injection. Variousembodiments of the invention encompass a maximum temperature of 60° C.,65° C., 70° C., and 80° C.

In any of the embodiments utilizing a pharmaceutical formulation, if theexcipients are expected to also diffuse from or be released from thelumen of the strut tube and into the body upon implantation, themolecular weight of an excipient may be chosen such that the excipientcan be excreted from the body via the kidneys if the excipient is not anexcipient which biodegrades in the body into fragments which can beexcreted from the body via the kidneys. In some embodiments, one or moreof the excipients, or all of the excipients, or all biostableexcipients, may have a number average molecular weight of less than40,000 Daltons, preferably less than 35,000 Daltons, and morepreferably, less than 30,000 Daltons.

In some embodiments, material may be injected into the strut tube afterside openings are formed in the tube. While the material is beinginjected into the tube, it may be desirable to cover and seal off theside openings, that is mask the side openings, to prevent leakage of thematerial. If the side openings are not sealed, or masked, during theinjection process, the material injected into one end of the tube maynot reach or flow to the opposite end of the tube. Masking or sealingthe side openings helps to minimize waste of the material, and helps toensure that the tube is filled completely and that the material isuniformly distributed throughout the tube. If the side openings areformed on the abluminal surface of the stent, the side openings can besealed by wrapping or encasing the abluminal surface with a thin sheetor thin tube of elastic material, which can be pressurized or shrunkdown onto the stent, such as, for example, by heat shrinking. If theside openings are formed on the luminal surface of the stent, the sideopenings can be sealed by wrapping or encasing the luminal surface witha thin sheet or thin tube of elastic material in the form of a balloonor a bladder that can be pressurized or inflated inside the tubularscaffolding of the stent.

In FIGS. 4A and 4B a device 150 is shown for sealing side openingsduring an injection process. In FIG. 4A, a stent 152 is shown adjacent acylindrical support 154 sized to fit within the tubular scaffolding ofthe stent. The cylindrical support 154 is attached to a gear system ormotor 156 for moving the cylindrical support axially along a rail 158.When the stent 152 is mounted on the cylindrical support 154, activationof the motor 156 allows the stent to be moved automatically in and outof the device 150.

The device 150 includes an elastic cover sleeve 160 and a manifold 162that together form a fluid filled plenum chamber 164. The elastic coversleeve 160 is in the shape of a cylindrical tube and has circularopenings at opposite ends of the sleeve. The opposite ends of the sleeve160 are fixedly connected to the manifold 162. The connection 161between the cover sleeve 160 and the manifold 162 is fluid tight. Theplenum chamber 164 is annular in shape and encircles the elastic coversleeve 160. The plenum chamber 164 can be filled with a gas or a liquid.The manifold includes a port hole 166 to allow movement of fluid intoand out of the plenum chamber 164. The elastic cover sleeve 160 has aninner diameter 170 and is configured to move from a first orientation asshown in FIG. 4A to a second orientation as shown in FIG. 4B. The innerdiameter 170 is greater when the elastic cover sleeve is in the firstorientation than when in the second orientation. The elastic coversleeve 160 is configured to move between the first orientation and thesecond orientation according to a change in fluid pressure inside theplenum chamber. The fluid pressure inside the plenum chamber 164 can beadjusted by a fluid pump 168 connected to the port hole 166.

When the elastic cover sleeve 160 is in the first orientation, as shownin FIG. 4A, the inner diameter 170 is greater than the outer diameter155 of the cylindrical support 154 and the outer diameter 153 of thetubular scaffolding of the stent 152 so as to allow the stent to bemoved into and out of the elastic cover sleeve 160 without makingcontact with the elastic cover sleeve 160. When the elastic cover sleeve160 is in the second orientation, the inner diameter 170 issubstantially the same as or is less than the outer diameter 155 of thecylindrical support 154 and the outer diameter 153 of the tubularscaffolding of the stent 152. In FIG. 4B, the inner diameter 170 of theelastic cover sleeve 160 presses against the stent 152 and is preventedin part from becoming smaller by the presence of the stent 152 andcylindrical support 154 within the elastic cover sleeve 160.

In use, the stent 152 is placed inside the elastic cover sleeve 160while in the first orientation. Next, fluid pressure inside the plenumchamber 164 is adjusted in such a way to cause or allow the elasticcover sleeve 160 to move toward the second orientation until the elasticcover sleeve presses against the abluminal surface of the stent andseals the side openings on the abluminal surface, as shown in FIG. 4B.The cylindrical support 154 prevents the tubular scaffolding of thestent from being crimped down to a smaller diameter by the pressureapplied by the elastic cover sleeve 160. An injector, such as shown inFIG. 2 or other device, is coupled to a stent strut (i.e., tube) such asshown in any one of FIGS. 3A-3D. While the elastic cover sleeve 160presses against the abluminal surface of the stent 152, the material isforced into the stent struts by the injector. Next, fluid pressureinside the plenum chamber 164 is adjusted in such a way to cause orallow the elastic cover sleeve 160 to move to the first orientation toallow removal of the stent from the device 150.

In some embodiments, the inner diameter 170 of the elastic cover sleeve160 is greater than the outer diameter 155 of the cylindrical support154 and the outer diameter 153 of tubular stent scaffold when theelastic cover 160 is an undeformed or natural state. When installed inthe manifold 162, the elastic cover sleeve 160 is configured to reduceits inner diameter 170 (i.e., move from the first orientation to thesecond orientation) with an increase of fluid pressure inside the plenumchamber 164. For example, while the stent 152 is inside the elasticcover sleeve 160, the fluid pump 168 can be activated by an electroniccontroller 174 to force fluid into the plenum chamber 164 and therebycause the elastic cover sleeve 160 to move from the first orientation(FIG. 4A) toward the second orientation and press against the abluminalsurface of the stent (FIG. 4B). After the material has been injectedinto the struts of the stent, the fluid pump 168 or a release valve 171is activated to allow fluid to exit the plenum chamber 164, which allowsthe elastic cover sleeve 160 to self-expand to the first orientation.Thereafter, the stent 152 can be removed from the device 150.

In other embodiments, the inner diameter 170 of the elastic cover sleeve160 is less than the outer diameter 153 of tubular stent scaffold whenthe elastic cover 160 is an undeformed or natural state. When installedin the manifold 162, the elastic cover sleeve 160 is configured toincrease its inner diameter 170 (i.e., move from the second orientationto the first orientation) with a decrease of fluid pressure inside theplenum chamber 154. For example, while the stent 152 is outside theelastic cover sleeve 160, the fluid pump 168 can vacuum fluid out of theplenum chamber 164 to cause the elastic cover sleeve 160 to move to thefirst orientation (FIG. 4A). Next, the stent 152 is placed into theelastic cover sleeve 160, then the fluid pump 168 or the release valve171 is activated to allow fluid to return into the plenum chamber 164,which allows the elastic cover sleeve 160 to self-contract toward thesecond orientation and press against the abluminal surface of the stent(FIG. 4B). After the material has been injected into the struts of thestent, the fluid pump 168 is again activated to vacuum fluid out of theplenum chamber 164 and cause the elastic cover sleeve 160 to move to thefirst orientation (FIG. 4A). Thereafter, the stent 152 can be removedfrom the device 150.

Referring again to FIGS. 4A and 4B, there is a pressure sensor 172inside the plenum chamber 164 configured to detect fluid pressure insidethe plenum chamber. The electronic controller 174 is in communicationwith the pressure sensor 172 and the fluid pump 168. The electroniccontroller 174 includes electrical circuits and may include acombination of electronic components, such as transistors, memorydevices, programmable logic controllers, microcontrollers and/ormicroprocessors. The controller 174 is configured to activate the fluidpump 168 based at least on an input signal from the pressure sensor 172.For example, the controller 174 can be configured to activate the fluidpump 168 so as to maintain a predetermined fluid pressure inside theplenum chamber 164 while the stent 152 is inside the elastic coversleeve 160. The predetermined fluid pressure can correspond to a desiredpressure that is applied by the elastic cover sleeve 160 on the stent152 to prevent damage to the stent or prevent the stent from beingcrimped to a smaller diameter.

In either the case of an external elastic cover sleeve to coverabluminal side openings or a balloon or bladder to cover the luminalside openings, the elastic cover sleeve, balloon, or bladder may be madefrom an elastomeric material that has sufficient mechanical strength towithstand the pressure of the composition within the lumen that passesout through the side openings as well as any external pressure appliedon to the elastomeric material to conform its shape to that of thestent. Examples of such materials include, without limitation: silicone;various types of polyurethane; styrene-isobutylene styrene triblockpolymers; thermoplastic polyester elastomers such as HYTREL®, a tradename of DuPont, some examples of which are poly(ether urea urethanes),poly(ester urethanes), poly(carbonate urethanes) poly(tetramethyleneglycol-co-butanediol-co-toluene diisocyanate), poly(dimethyl siloxane);thermoplastic elastomer nylon copolymer such as PEBAX®, which is a tradename of Arkema Group for polyether block amide thermoplastic elastomers,some examples of which are copolymers of nylon-12 andpoly(tetramethylene glycol) and copolymers of poly(ethylene glycol) andnylon-6. Another possible material that may be used for either theballoon or the sleeve is heat shrink tubing such as crosslinkedpolyethylene. The material of the balloon and/or the sleeve may notabsorb a significant quantity of the therapeutic agent and/or optionalexcipient. If the material injected is an injection solution whichincludes a solvent, the elastomeric material may not swell to anyappreciable extent in the solvent. In some embodiments, the extent ofswelling by any one of or any combination of the solvent, thetherapeutic agent, and the optional excipient may be less than 10% byweight, preferably less than 2% by weight, and even more preferably,less than 1% by weight.

In FIGS. 5A-5C a device 180 is shown to prevent the material beingfilled into strut tubes during an injection process from escaping outthrough side openings 181 formed into the strut tubes. In FIG. 5A, astent 182 is shown carried on a cylindrical support 184 sized to fitwithin the tubular scaffolding of the stent. The entire stent 182 isdisposed within the pressure chamber 190 throughout the injectionprocess. The cylindrical support 184 is attached to a gear system ormotor 186 for moving the cylindrical support axially along a rail 188,the direction of movement being parallel to the longitudinal, centralaxis 189 of the stent. When the stent 182 is mounted on the cylindricalsupport 184, activation of the motor 186 allows the stent to be movedautomatically within the pressure chamber 190. Movement of the stentwithin the pressure chamber alters the surrounding fluid pressureexperienced by the stent, as will be explained below. The pressurechamber 190 has a conical shape such that its curved inner surface 191is tapered and reduces in diameter between opposite ends of the chamber.The pressure chamber 190 has a relatively narrow end 192 and arelatively wide end 194.

In other embodiments, the pressure chamber 190 is cylindrical such thatits curved inner surface 191 is not tapered and has a uniform diameterbetween opposite ends of the pressure chamber.

As shown in FIG. 5B the exemplary pressure chamber 190 has a circularcross-section. The stent 182 and the cylindrical support 184 areradially centered within the curved inner surface 191 of the pressurechamber. A gap that serves as a gas flow path 196 exists radiallybetween the stent 182 and the curved inner surface 191. The gas flowpath 196 completely encircles the stent 182. The gas flow path 196 has asubstantially annular shape in radial cross-section as shown in FIG. 5B.The annular shape is bounded by the outer surface 185 of the cylindricalsupport 184 and the curved inner surface 191 of the pressure chamber190. The gas flow path 196 has a radial cross-sectional area thatincreases from the narrow end 192 to the wide end 194 of the pressurechamber 190.

A gas supply or pump 198 is connected by a conduit to the narrow end 192of the pressure chamber 190. The gas pump 198 is configured to force gasthrough the conduit and into the pressure chamber 190 when the gas pumpis activated. The gas forced into the pressure chamber 190 exits at theopposite end of the pressure chamber through a gas outlet 199 at thewide end 194.

In the illustrated embodiment, the entire stent 182 is formed of acontinuous, coiled tube 183. Various segments of the coiled tube 183serve as stent struts that are connected end to end to collectively formthe stent scaffolding for supporting biological tissue afterimplantation within a patient. The opposite ends of the coiled tube 183have tube openings. The tube opening closest the narrow end 192 of thepressure chamber 190 is connected to an injector 200. The injector 200is configured to force the material into the coiled tube 183 when theinjector 200 is activated. The tube opening closest the wide end 194 ofthe pressure chamber 190 is connected to a gas conduit 201 that leads tothe exterior of the pressure chamber 190. The gas conduit 201 allowsfluid pressure at the tube opening of the coiled tube 183 closest thewide end 194 to equalize with ambient pressure outside the pressurechamber 190.

The injector 200 and the gas conduit 201 can be connected to the coiledtube 183 in various ways shown in FIGS. 3A-3D or by other methods. Theinjector 102 in FIGS. 3A-3D would be replaced by the injector 200 or thegas conduit 201. The injector 200, cylindrical support 184, and the gasconduit 201 pass through fluid-tight seals in apertures formed throughwalls of the pressure chamber 190.

There are a plurality of side openings 181 on the abluminal surface ofthe stent. The side openings 181 are spaced apart from each other andare distributed along the entire longitudinal length of the stent 182.The side openings 181 extend into and provide access to the lumen of thecoiled tube 183 of the stent. The side openings 181 allow a compositionthat is filled into the coiled tube 183 to diffuse or disperse out at alater time, such as after the stent is implanted within a patient.

The coiled tube 183 initially contains only gas at the start of theinjection process. When the injector 200 is activated, the material isforced into the stent 182 through the tube opening closest the narrowend 192, which creates an internal fluid pressure gradient within thecoiled tube 183. The internal pressure gradient corresponds to arelatively high fluid pressure within the tube opening attached to theinjector 200 and a relatively low fluid pressure at the tube openingattached to the gas conduit 201.

It will be appreciated that the material may begin to spill out of theside openings 181 during the injection process. To inhibit or preventthe material from spilling out of the side openings 181, an externalfluid pressure gradient is created outside of the coiled tube 183 by gasflow through the pressure chamber 190. The words “internal” and“external” when used to modify the phrase “pressure gradient” refer tofluid pressure gradients that exist inside and outside the coiled tube183, respectively.

As gas is forced into the narrow end 192 of the pressure chamber 190,the gas flows longitudinally from the narrow end 192 to the wide end 194where it exits the pressure chamber 190. The fluid pressure in variouslongitudinal locations (along the x-axis shown in FIG. 5A) within thepressure chamber 190 (and external to the coiled tube 183) depends atleast in part on resistance to gas flow at the respective location, andresistance to gas flow depends at least in part on the radialcross-sectional area of the gas flow path 196 at the respectivelocation. The gas flow creates the external fluid pressure gradient in alongitudinal direction due to the decreasing resistance to gas flowarising from the increase in the cross-sectional area of the gas flowpath 196 from the narrow end 192 to the wide end 194. The fluid pressuresurrounding the stent will be greater at longitudinal locations near thenarrow end 192 than at longitudinal locations near the wide end 194.Preferably, the external pressure gradient substantially matches theinternal pressure gradient so that at any particular longitudinallocation intersecting the stent 182, the fluid pressure inside thecoiled tube 183 is substantially equal to the fluid pressure outside thecoiled tube. The composition is inhibited or prevented from spilling outof the side openings when, during the injection process, the pressureinside the coiled tube 138 and the pressure outside the coiled tube aresubstantially equal to each other.

A first set of pressure sensors 202 are longitudinally distributed andspaced apart from each other and disposed within the pressure chamber190 to provide a measurement of the external pressure gradient. Thepressure sensors 190 may be coupled to the cylindrical support 184 sothat they move with the stent 183. Another set of pressure sensors 203are disposed on the injector 200 and the gas conduit 201 to provide ameasurement of the internal pressure gradient. Both sets of pressuresensors 202, 203, the injector 200, the gas pump 198, and the motor 186are in communication with an electronic controller 204, which includeselectrical circuits and may include a combination of electroniccomponents, such as transistors, memory devices, programmable logiccontrollers, microcontrollers and/or microprocessors. The controller 204is configured to simultaneously activate the gas pump 198, the injector200, and/or the motor 186 based at least on an input signal from one orboth sets of pressure sensors 202, 203 so that internal and externalpressure gradients substantially match each other. For example, theinternal and external pressure gradients may be matched by having thecontroller 204 reduce or increase the flow of gas from the gas pump 198,reduce or increase the flow of the composition into the coiled tube 183,and/or move the stent 182 longitudinally within the pressure chamber190.

The internal pressure gradient (i.e., the pressure gradient that existinside the coiled tube 183) may not be static during the injectionprocess. That is, the pressure gradient profile may change in shapeand/or value as the material is injected into and moves through thecoiled tube 183. For example, FIGS. 5D and 5E, depict the internal andexternal pressure gradients as curves Pi and Pe, respectively, as afunction of longitudinal position X within the coiled tube 183. FIG. 5Ddepicts the internal and external pressure gradients when the stent isat the position shown in FIG. 5A and material 207 is just starting to beinjected into the coiled tube 183 at location X1. FIG. 5E depicts theinternal and external pressure gradients at a later time, when the stentis at the position shown in FIG. 5C and the material 207 has reachedlocation X2 within the coiled tube 183. The internal and externalpressure gradients Pi and Pe have shifted upwards in FIG. 5E, indicatinga rise in pressure from FIG. 5D.

To keep the external pressure gradient Pe (i.e., the pressure gradientthat exists outside the coiled tube 183) matched with the internalpressure gradient Pi, the controller 204 may, as the material movesthrough the coiled tube 183, reduce or increase the flow of gas from thegas pump 198, reduce or increase the flow of the material into thecoiled tube 183, and/or move the stent 182 longitudinally within thepressure chamber 190. For example and not limitation, in cases where theinternal pressure gradient increases during the injection process, thecontroller 204 may cause the stent 182 to longitudinally move inaccordance with input from one or both sets of pressure sensors 202,203. Simultaneously while the material is injected into the coiled tubeopening 205 closest the narrow end 192, the longitudinal stent movementcan be from a first position close to the wide end 194 of the pressurechamber 190 (such as shown in FIG. 5A) to a second position close thenarrow end 192 of the pressure chamber (such as shown in FIG. 5B). Theabove described method of injecting material into opening 205 and movingthe stent toward the narrow end 192 of the chamber 190 corresponds toCase 1 in TABLE 1.

TABLE 1 Injector Travel Direction of Travel Direction of connectedMaterial Injected Stent while Material to Stent into Stent is InjectedCase 1 At Opening 205 From Opening 205 to From FIG. 5A Opening 206 toFIG. 5C Case 2 At Opening 205 From Opening 205 to From FIG. 5C Opening206 to FIG. 5A Case 3 At Opening 206 From Opening 206 to From FIG. 5AOpening 205 to FIG. 5C Case 4 At Opening 206 From Opening 206 to FromFIG. 5C Opening 205 to FIG. 5A

In other embodiments, the injection process proceeds according to Case 2in TABLE 1. Simultaneously while the material is injected into thecoiled tube opening 205 closest the narrow end 192, the longitudinalstent movement can be from a first position close to the narrow end 192of the pressure chamber 190 (such as shown in FIG. 5C) to a secondposition close the wide end 194 of the pressure chamber (such as shownin FIG. 5A).

In other embodiments, the injection process proceeds according to Case 3in TABLE 1. The injector 200 is connected to the coiled tube opening 206closest the wide end 194 (instead of being connected to the coiled tubeopening 205 closest the narrow end 192, as shown in FIGS. 5A and 5B).Simultaneously while the material is injected into the coiled tubeopening 206 closest the wide end 194, the longitudinal stent movementcan be from a first position close to the wide end 194 of the pressurechamber 190 (such as shown in FIG. 5A) to a second position close thenarrow end 192 of the pressure chamber (such as shown in FIG. 5C).

In other embodiments, the injection process proceeds according to Case 4in TABLE 1. The injector 200 is connected to the coiled tube opening 206closest the wide end 194. Simultaneously while the material is injectedinto the coiled tube opening 206 closest the wide end 194, thelongitudinal stent movement can be from a first position close to thenarrow end 192 of the pressure chamber 190 (such as shown in FIG. 5C) toa second position close the wide end 194 of the pressure chamber (suchas shown in FIG. 5A).

In the illustrated embodiment, the pressure chamber 190 has afrustoconical shape. The particular shape of the curved inner surface191 is selected to provide a desired pressure gradient longitudinallyacross the chamber. It will be appreciated that shapes for the curvedinner surface 191 other than what is illustrated herein may beimplemented to provide a desired pressure gradient. In alternativeembodiments, for example, the longitudinal cross-sectional profile ofthe curved inner surface 191 may be concave or convex instead of thestraight cross-sectional profile shown in FIGS. 5A and 5C. In someembodiments, the longitudinal cross-sectional profile of the curvedinner surface 191 can have abrupt changes in diameter so as to producesteps or notches instead of the continuous and gradual change indiameter shown in FIGS. 5A and 5C.

In another embodiment, the masking or sealing of the side openings maybe accomplished by applying a thin layer of a water soluble and/orbio-absorbable coating over the strut tube or the stent. The coatingwould bridge or cover the holes, and optionally may fill the holes.Therefore the coating would not be a conformal coating over the entireouter surface of the strut tube, but would conform to the outer surfaceexcept for the side openings, which may be bridged or webbed over, andoptionally may be completely or partially filled. The coating wouldremain on the stent in effect masking or sealing the side openings untilimplanted at which time it would dissolve, or degrade. Thus, the coatingwould prevent and/or limit the leakage of the material during injectionand would also prevent or limit leaking of the composition filling thelumen of the strut tubes during storage of the device. In someembodiments, the side openings may be plugged, or filled, eitherpartially, completely, or essentially completely, with a bioabsorablematerial to prevent or limit the leakage of material during injection,and to prevent or to limit the leakage of the composition duringstorage. In some embodiments, at least 95 wt %, at least 98 wt %, or atleast 99 wt % of the composition remains within the lumen of the struttube at the end of a storage time period. The storage time period may be6 months, 12 months, 18 months, or 24 months. Materials useful for thethin water soluble and/or bioabsorable coating include, withoutlimitation, poly(ethylene oxide), poly(ethylene glycol), PLURONIC®polymers, poly(vinyl pyrrolidone), gelatin, poly(2-hydroxyethylmethylmethacrylate), dextrose, dextran, poly(vinyl alcohol),poly(glycolide), poly(D,L-lactide-co-glycolide),poly(L-lactide-co-glycolide), poly(caprolactone-co-glycolide),poly(anhydrides), and poly(orthoesters).

In some embodiments, a water soluble and/or bio-absorbable coating isapplied over the strut tube or the stent prior to the loading of acomposition into the lumen of the strut tube, and in such embodiments,the viscosity of the composition filling the lumen of the strut tube maybe lower than without a coating as the coating may prevent the leakageof the composition from the side openings during storage and duringloading. In those embodiments in which a water soluble and/orbio-absorbable coating is applied to the strut tube prior to loading,the viscosity of the composition filling the strut tube at a temperatureof approximately 20° C. to 25° C. and one atmosphere may be below 100 cPsuch as from about 1 cP to about 5 cP, about 5 cP to about 10 cP, about5 cP to about 20 cP, about 10 cP to about 50 cP, about 20 cP to about 80cP, about 50 cP to about 100 cP, or greater than 100 cP. In otherembodiments, the viscosity at a temperature of approximately 20° C. to25° C. and one atmosphere may be about 10 cP to about 1000 cP. In someof the embodiments in which the coating is applied prior to loading, thecomposition may have a viscosity of not less than 100 cP, not less than200 cP, or not less than 1000 cP. In those embodiments using a watersoluble and/or bio-absorbable coating, the composition that is loadedinto the lumen of a strut tube, the extent of swelling by any one of orany combination of the solvent, the therapeutic agent, and the optionalexcipient may be less than 10% by weight, preferably less than 2% byweight, and even more preferably, less than 1% by weight where the %swelling is determined after 3 months storage at a temperature of 25° C.or an equivalent thereof. In some embodiments, the excipient and/ortherapeutic agent may not migrate into the coating to an appreciableextent (a mass increase of the coating of more than about 10%), while inother embodiments, the excipient and/or therapeutic agent may migrateinto the coating.

Embodiments of the present invention encompass injection of an injectionsolution as well as injection of a composition such as, for example,those described above.

A composition may be loaded into a strut tube in a number of other ways,as an alternative to pushing or displacing material into a strut tube.For example, pressure outside or inside the strut tube can be decreasedto draw gas out of the strut tube and draw material into the strut tube.In some embodiments, material may be injected into one opening using apressure greater than that of the surrounding environment and at thesame time a vacuum may be applied at another opening to assist infilling the lumen. Thus, for any of the above injection methods,alternative embodiments exist in which the material may be drawn intothe lumen via a decrease in pressure, such as for example, by applying avacuum, and other embodiments encompass methods using both injection andapplication of a vacuum.

In FIG. 6, fluid pressure outside the strut tube is decreased to a levelbelow fluid pressure inside the strut tube. Material can be drawn intothe strut tube through an opening at the end of the strut tube, throughside openings in the tube, or through both end openings and sideopenings. An apparatus 210 for loading material into a stent structurecomprises a vacuum chamber 212 that contains a material 214 that issupplied to the vacuum chamber by a first conduit 216 connected to areservoir 218 or other source of additional material. A second conduit220 connects the vacuum chamber 212 to a pump 222 configured to reducepressure inside the vacuum chamber when the pump is activated. Apressure sensor 223 inside the vacuum chamber 212 is configured todetect pressure inside the vacuum chamber. An electronic controller 230is in communication with the pressure sensor 223 and the pump 222, andis configured to activate the pump based at least on an input signalfrom the pressure sensor. The electronic controller 230 includeselectrical circuits and may include a combination of electroniccomponents, such as transistors, memory devices, programmable logiccontrollers, microcontrollers and/or microprocessors.

A stent 224 is disposed inside vacuum chamber 212. An exemplary stentcomprises a tubular scaffolding formed from a plurality of strut tubesformed from a continuous tube into which the material 214 is to beloaded. The strut tubes have at least one opening immersed in thematerial 214. In the illustrated embodiment, the entire stent 224 isimmersed in the material 214 such as may be desired when a plurality ofside openings have been formed throughout the stent. The stent 224 issupported by a cylindrical support 225 for transporting the stent intoand out of the vacuum chamber 212. Internal dimensions of the vacuumchamber are sized to accommodate the cylindrical support 225. Thecylindrical support 225 is sized to fit within the central lumen of thetubular scaffolding of the stent 224 and is configured to keep the stentimmersed in the material 214 in the vacuum chamber 212.

Initially, the strut tubes of the stent 224 are gas-filled. When thestent is immersed into the material 214, the material 214 may not enterall parts of the strut tubes due to gas entrapped inside the struttubes, viscous resistance, and capillary forces. Before the pump 222 isactivated, the fluid pressure inside the strut tubes is substantiallythe same as the fluid pressure inside the vacuum chamber 212. Next, thepump 222 is activated so that gas inside the vacuum chamber 212 is drawnout of the vacuum chamber, which makes the pressure inside the vacuumchamber and fluid surrounding the strut tubes lower than pressure insidethe strut tubes. The difference in pressure causes the previouslyentrapped gas to exit the strut tubes thereby allowing the material 214to fill the strut tubes. After the strut tubes are filled with thematerial 214, the pump 222 or a valve 226 is activated to allow gas toflow back into the vacuum chamber 212 and thereby allow the fluidpressure inside the vacuum chamber 212 to equalize with ambientpressure. The valve 226 is coupled to a vent formed into the wall of thepressure chamber 212. In some instances, after a vacuum is applied, thestrut tubes are evacuated and have essentially a vacuum inside them.Then, when the pressure of chamber 212 is equalized with ambientpressure, such as by opening of the valve 226, the material 214 isdriven into the strut tubes. This process may be repeated if necessaryto effect complete loading of material 214 into the strut tubes.Thereafter, the stent 224 is removed from the vacuum chamber 212.

Still referring to FIG. 6, the apparatus 210 also includes a temperaturecontrol device 228 configured to cool down or lower the temperature ofthe material 214 inside the vacuum chamber 212, as may be desired whenthe material includes a volatile liquid. A temperature sensor 229 insidethe vacuum chamber is configured to detect temperature of the material214. The controller 230 is in communication with the temperature sensor229 and the temperature control device 228, and is configured toactivate a cooling element in the temperature control device, based atleast on an input signal from the temperature sensor, so that thetemperature control device 228 cools the material inside the vacuumchamber 212. The controller 230 can activate the cooling element to keepany volatile liquid in the material 214 from boiling when pressureinside the vacuum chamber is being reduced by the pump 222. In thisembodiment, the temperature control device 228 functions as a coolingdevice.

In other embodiments, the controller 230 is configured to activate aheating element in the temperature control device 228, based at least onan input signal from the temperature sensor, so that the temperaturecontrol device 228 heats the material inside the vacuum chamber 212. Thecontroller 230 can activate the heating element in order to reduce theviscosity of the material in the vacuum chamber and to make it easierfor the material to flow into the opening to the lumen. In thisembodiment, the temperature control device 228 functions as a heatingdevice.

Another embodiment is illustrated in FIG. 7. In FIG. 7, fluid pressureinside the strut tubes is decreased to a level below fluid pressureoutside the strut tubes. Material is drawn into the strut tubes throughside openings in the tube. An apparatus 250 for loading material into astent structure comprises container 252 of material 254 that is suppliedto the container by a supply conduit 256 connected to a reservoir 258 orother source of additional material. The container 252 has a removablelid 253. Internal dimensions of the container 252 are sized to allowplacement of a stent 260 inside the container. In the illustratedembodiment, the entire stent 260 is formed of a continuous, coiled tube262. Various segments of the coiled tube 262 serve as stent struts thatare connected end to end to collectively form the stent scaffolding forsupporting biological tissue after implantation within a patient. Theends 264 of the coiled tube 262 are shown immersed in the material 254but need not be immersed in order to fill the coiled tube with thematerial. There are openings at opposite ends 264 of the coiled tube262. Two gas conduits 268 connect the tube openings at the opposite ends264 of the coiled tube 262 to a suction pump 270 configured to suctiongas when the pump is activated. The gas conduits 268 can be connected tothe coiled tube 262 in various ways shown in FIGS. 3A-3D or by othermethods. The injector 102 in FIGS. 3A-3D would be replaced by the gasconduits 268.

There are a plurality of side openings 266 (holes and/or pores) spacedapart along the length of the coiled tube 262. The side openings 266 areimmersed in the material 254 to allow material 254 to fill the coiledtube 262.

Initially, the coiled tube 262 of the stent 260 is gas-filled. The stent260 is connected to the gas conduits 268 and immersed into the material254. The material 254 may not enter all parts of the coiled tube 262 dueto gas entrapped inside the coiled tube. Before the suction pump 270 isactivated, the pressure inside the coiled tube is substantially the sameas the pressure inside the container 252. Next, the suction pump 270 isactivated by an electronic controller 276 so that gas inside the coiledtube 262 is drawn out, which makes the fluid pressure inside the coiledtube lower than the fluid pressure of the fluid 254 surrounding thecoiled tube. Drawing out the previously entrapped gas through the gasconduits 268 causes the material 254 to be drawn into the side openings266 and thereby fill the coiled tube.

After the coiled tube is filled with the material 254, material 254 willbegin to be drawn into the gas conduits 268. There are sensors 272disposed on the gas conduits 268 for detecting the presence of material254 inside the gas conduits 268. There is also a valve 274 whichconnects the gas conduits 268 to the suction pump 270. The electroniccontroller 276 is in communication with the suction pump 270, thesensors 272, and the valve 274. The electronic controller 276 includeselectrical circuits and may include a combination of electroniccomponents, such as transistors, memory devices, programmable logiccontrollers, microcontrollers and/or microprocessors. The controller 276is configured control the suction pump 270 and the valve 274 based atleast on an input signal from the sensors 272. For example, when onlyone of the sensors 272 detects the presence of material 254 inside oneof the gas conduits 268, the controller 276 activates the valve 274 soas to stop suction in the material-filled gas conduit while stillallowing suction to continue in the other gas conduit. After the coiledtube 262 is completely filled, as indicated by the presence of material254 inside both gas conduits 268, the coiled tube 262 is removed fromthe container 262 and disconnected from the gas conduits 268.

The filling process can include actively lowering the fluid pressureinside the coiled tube 262, as already described above, whilesimultaneously increasing the fluid pressure of the material 254surrounding the coiled tube 262, as will be described below.

There is a pressure sensor 280 inside the container 252 configureddetect fluid pressure of the material 254. There is a supply pump 282along the supply conduit 256 configured to force the material 254 intothe container 252 when the supply pump is activated. The controller 276is configured control the supply pump 282 based at least on an inputsignal from the pressure sensor 280. For example, the controller 276 canbe configured to activate the suction pump 270 while simultaneouslyactivating the supply pump 282, thereby increasing the difference influid pressure between inside and outside of the coiled tube 262. Thesupply pump 282 is controlled in such a way by the controller 276 sothat a predetermined fluid pressure of the material 254 is maintainedduring the filling process.

There is a gas supply conduit 284 connecting the container 252 to a gassupply pump 286 configured to force gas into the container when the gassupply pump is activated. The controller 276 is configured control thegas supply pump 286 based at least on an input signal from the pressuresensor 280. For example, the controller 276 can be configured toactivate the suction pump 270 while simultaneously activating the gassupply pump 286, thereby increasing the difference in fluid pressurebetween inside and outside of the coiled tube 262. The gas supply pump286 is controlled in such a way by the controller 276 so that apredetermined fluid pressure of the material 254 is maintained duringthe filling process.

There is optionally a temperature sensor 290, such as and withoutlimitation a thermocouple or resistance temperature detector, inside thecontainer 252 configured to detect the temperature of the material 254.There is a heating and/or cooling element 292, such as for example andwithout limitation, a coil through which a heating fluid or a coolingfluid may flow, inside the container 252 configured to heat or cool thematerial 254. The controller 276 is configured control the heating orcooling element 292 based at least on an input signal from thetemperature sensor 290.

In alternative embodiments, the container 252 can be an open or closedcontainer without any means for controlling the pressure of the material254. In such embodiments, the apparatus 260 includes no supply pump 282and no gas supply pump 286.

In alternative embodiments, the stent 260 is carried on a cylindricalsupport that transports the stent down into and up out of the container252. Such a cylindrical support is configured to keep the stent immersedin the material 254. Such a cylindrical support is connected to a geararrangement or a motor which is coupled to a rail. Such a cylindricalsupport can be configured in the same manner as the cylindrical support154 of FIGS. 4A and 4B.

In alternative embodiments, the sensors 272 are configured to detect thepresence of gas bubbles in the gas conduits 268. The suction pump 270 iscontrolled by the controller 276 so that the suction pump 270 draws thematerial carried by the container 252 into the side openings 266 to thelumen and into the gas conduits 268. The controller 276 causes thesuction pump 270 to continue drawing the material until gas bubblescease to pass from the lumen of the stent 260 and into the gas conduits268. The absence of gas bubbles can indicate that the lumen of the stent260 is completely filled with the material. The controller 276 can beconfigured to stop the suction pump 270 based at least on an indicationfrom the sensors 272 of the absence of air bubbles. Optionally, thesuction pump 270 can be a positive displacement pump, such as a gearpump, which is configured to draw the material from the gas conduits 268(having passed through the lumen of the stent 260) and return thematerial back into the container 252.

For those embodiments in which the stent is immersed in material, afterit has been loaded with the material, the stent may be removed from thematerial and any material or components thereof adhering to the outersurface of the stent may be removed. The methods of removal include, forexample and without limitation, wiping the exterior with a cloth,brushing, wiping, blowing, rinsing, application of a high DC voltage, orcentrifuging the material or components therefore from the outer surfaceof the stent, or any combination thereof. The removal is accomplishedwithout or with minimal removal (for example, without limitation, lessthan 5 wt %) of the composition within the lumens of the strut tubes ofthe stent. If the material is at a temperature above about 20° C., theremoval may occur prior to, after, and/or simultaneous with cooling ofthe stent and its contents. If the material is an injection solution,the removal may occur before, after, and/or simultaneous with thealteration of the condition of temperature and pressure. As anon-limiting example, the stent may be removed from the solution, andthe condition of temperature and pressure changed resulting in thedeposition of a composition including a therapeutic agent into the lumenand potentially also onto the outer surface of the stent. The stent maythen be rinsed with a solvent which may be the same as or different fromthe solvent of the injection solution, or the stent may be wiped toremove the composition adhering to the exterior of the stent.

The material that may be pushed or drawn into the lumen of thestructural element for any of the above described apparatuses (e.g.FIGS. 4, 5, 6, and 7) may be any of the compositions described above foruse in the injection methods or the material may be an injectionsolution as described above. In some embodiments, the material may be atherapeutic agent that has been melted. In other embodiments, thematerial may be a pharmaceutical formulation including a therapeuticagent and an excipient such as for example a low melting excipient, asdescribed above. In still other embodiments, the material may be a highviscosity pharmaceutical formulation. For either of the first twoscenarios, that is the molten therapeutic agent or pharmaceuticalformulation with a low melting excipient, the material 254 in thecontainer 252 may be heated to a temperature, or within a temperaturerange, sufficient to maintain the material in a fluid state. For thehigh viscosity pharmaceutical formulation, the material may beoptionally heated. In some embodiments, if the material 254 is a highviscosity pharmaceutical formulation, the material 254 is heated to aspecific temperature to maintain the viscosity at or below a specifiedviscosity, for example and without limitation, 100 cP at a pressure ofone atmosphere pressure. For any of compositions discussed above, thematerial 254 in the container 252 may be heated to a specifictemperature and maintained at or above the specific temperature, wherethe specific temperature may be at or about 30° C., at or about 35° C.,at or about 40° C., at or about 45° C., or higher. For the compositionwhich is either a molten therapeutic agent or a pharmaceuticalformulation including a therapeutic agent and a low melting excipient,the specific temperature may be the melting temperature of thetherapeutic agent, the melting temperature of the pharmaceuticalformulation, or the melting temperature of the excipient, or higher, andin still other embodiments the specific temperature may be 5° C., 10°C., or 15° C. higher than the melting temperature of the therapeuticagent, the pharmaceutical formulation, or the excipient. For the case inwhich the material is any of the above compositions, the temperatureused may be one that avoids, or limits, significant degradation of thetherapeutic agent, or limits the degradation to not more than 3 wt % ornot more than 1 wt %.

If the material is heated, the stent, filled with a composition asdescribed above, may be cooled to a temperature of approximately 20° C.to 25° C. and one atmosphere as previously described, after removal fromthe container 252.

If the material is a high viscosity pharmaceutical formulation, the sizeof the therapeutic agent particles, if the therapeutic agent isdispersed in the excipient, and/or if the therapeutic agent is added asa particle, may be such that the particles do not plug the side openingsupon filling the lumen.

In other embodiments the material 254 in the container 252 may be aninjection solution as described previously, that is a compositionincluding a therapeutic agent, and optionally an excipient, dissolvedand/or dispersed in a solvent. As for the injection solution describedpreviously, the solvent used may be one that is in a gas phase at about20° C. to 25° C. and one atmosphere, and therefore, readily evaporates.The container 252 and the material 254 may be maintained at a conditionof temperature and pressure such that the material, which is aninjection solution, remains in a liquid or supercritical state. Once thelumen of the stent structure is filled with the injection solution andthe stent has been removed from the container, the condition of thestent may be altered or changed such that the stent and compositiontherein is at about 20° C. to about 25° C. and one atmosphere. Undersuch a condition the solvent readily evaporates leaving the compositionwithin the lumen of the strut tubes of the stent.

If the material 254 in container 252 is an injection solution, to fillthe lumen with a desired quantity of the composition, there may be aneed to subject the stent to more than one cycle of immersion in thematerial, removal from the material, and alteration of the condition ofpressure and temperature. The cycle may, optionally, also include anoperation to remove the composition and/or solvent from the outersurface of the stent. In subsequent immersion cycles, it is potentiallypossible for the composition that has already been deposited in thelumen to be re-dissolved into the injection solution. To limit orprevent this occurrence, the injection solution may be near or at thesaturation limit of the therapeutic agent and/or the optional excipient.

In any of the above embodiments, one or more openings, for example andwithout limitation, an opening at end 264 as shown in FIG. 7, may betemporarily plugged before immersion into the material or immediatelyafter removal from the material. If the material is an injectionsolution, one or both openings, if more than one opening is present, atthe end of the tube may be plugged soon after removal from the solution,followed by the change in the condition of temperature and pressure, andthen followed by removal of the plugs after the solvent has evaporatedor has substantially evaporated.

As with the methods involving injection, any of the immersion methodsdiscussed above may be performed in an inert atmosphere and/or lowhumidity atmosphere as described previously.

Once the strut tube is filled with a composition by any of the methodsdescribed above, the opening(s), for example and without limitation theinlet openings at the ends of the tube, may be sealed. The ends may besealed by mechanical sealing the ends. A mechanical seal involvescrimping or compressing the ends down to seal, or essentially seal, theopening. FIGS. 8A and 8B illustrate the end view of an opening at theend of a strut tube, and a sealed end. As shown in FIGS. 8A and 8B, theedge 1018 of the tube may be circular or approximately circular in shapebefore crimping as shown in FIG. 8A, and after crimping, may beessentially a linear or rectangular shape as shown in FIG. 8B. The endsmay be crimped together, welded together, or both crimped and welded.The end may be sealed by welding it to an adjacent strut tube.

Alternatively, the ends may be plugged or capped. A plug may be anobject which is designed to fit into a hole tightly, and generallyprevents liquid or fluid from passing through the hole. FIGS. 9A and 9Bare exemplary and non-limiting examples of plugs 1022 and 1030,respectively, and FIG. 9C is an exemplary embodiment of a cap 1040 foran open end of a tube 100. Plugs 1022 and 1030 each have a smallerdiameter, 1024, and a larger diameter 1028. For plug 1022 which isessentially the shape of a truncated cone, the smaller diameter 1024 isless than that of the diameter of the lumen of the tube 1034, and thelarger diameter 1028 is greater than that of the lumen of the tube, andmay be greater than the outer diameter 124 of tube 100. For plug 1030,the smaller diameter 1024 is equal to, slightly less than, or slightlygreater than the inner diameter of the lumen of the tube 1034 and thelarger diameter of the plug 1028 is sufficiently greater than thesmaller diameter 1024 to prevent the plug from being pushed entirelyinto the lumen. Plug 1030 has the shape of two concentrically stackedcylinders in which the cylinder with the larger diameter 1028 has aheight/diameter ratio<1, preferably <0.5, and even more preferably,<0.25. The cylinder of the smaller diameter 1024 has a height/diameterratio that is at least 0.25, preferably 0.5 or greater, and which may be1 or more.

The cap 1040 is in the shape of essentially a cylinder having acylindrical hole concentrically counter bored in the center. The cap1040 also has a smaller diameter 1024 which is equal to, or slightlysmaller than the outer diameter 124 of the tube. The cap may stay on theend of the tube by compression fitting. The length of the side 1036 ofthe cap should be sufficient to keep cap on the end of the tube, and theratio of the side 1036 to the thickness of the top 1038 may be 1.5 ormore. The larger diameter 1028 of cap 1040 is a function of the smallerdiameter 1024 and the wall thickness 1029 of sides of the cap.

A plug may be placed in the end of the tube preventing material, such asa composition, from flowing out of the end. The plugs or caps may betemporary or intended to remain on during implantation, that isessentially permanent. The plug or cap may be polymeric, metallic,ceramic, glass, another material, or any combination thereof. Inpreferred embodiments, the plug or cap is made from, that is entirely,polymeric, or it consists essentially of, a polymer. In the variousembodiments, the polymer may be a water soluble polymer, a biostablepolymer, a biodegradable polymer, or a combination thereof. If abiostable polymer is used for the plug or cap, the polymer may berelatively impermeable to the therapeutic agent and optional excipient.As used herein, “relatively impermeable” with respect to the propertiesof the biostable polymer plug or cap may be a weight gain of less than5% over the course of 24 months in storage under controlled roomtemperature as defined by the USP, or may be a plug, that if used toseal one or more openings in a stent that has been filled with acomposition, retains, at least 95 wt % of the initial composition weightthe stent after 24 months in storage under controlled room temperatureas defined by the USP. In some embodiments, plugs or caps may beselected such that when used to seal one or more openings in a stentthat has been filled with a composition, retains, at least 97 wt %, orat least 98%, of the initial composition weight after 24 months instorage under USP controlled room temperature.

With respect to the embodiments of the present invention, the term“plugged” will be used but embodiments also encompass having the ends“capped.”

In some embodiments, at least one opening, such as, for example andwithout limitation, an inlet opening at an end of the tube, may beplugged or capped prior to the injection of a material. Similarly, ifthe end is plugged prior to injecting the injection solution, the plugor cap, whether including a biostable polymer, a biodegradable polymer,or both, and/or other materials, may not more 10% by weight, preferablynot more than 5% by weight, and even more preferably, not more than 1%by weight solvent and/or the composition of a therapeutic agent and anoptional excipient, over the course of the injection, and optionally forsome time period after the injection. For a biodegradable plug or cap,weight gain after implantation may occur as a result of water absorptionby the plug or cap.

In some embodiments, the both ends of the tube are sealed and theinjection or immersion may occur primarily through the side openings. Insuch embodiments, only some of the sidewall openings may be masked whileothers are used for injection and still others are left open to allowair to escape and/or a vacuum may be applied.

Once the strut tubes of a stent have been filled with a composition andsome openings optionally sealed, the outer surface, or at least aportion of the outer surface of, a stent having hollow struts may becoated. The coating may be polymeric, metallic, glass, ceramic, othermaterial, or any combination thereof. In preferred embodiments, thecoating includes a polymer. A typical coating process involvesdissolving and/or dispersing the coating materials, such as, forexample, a polymer, optionally with other excipients and/or atherapeutic agent, in a solvent to form a coating solution, anddisposing the coating solution over the outer surface of the stent byprocedures such as spraying, brushing, wiping or directly depositing thesolution onto the surface of the stent. The solution may be applied byimmersing the stent in the solution. Non-limiting examples of otherprocesses of applying a coating, which may or may not include a solvent,are plasma deposition processes, electrostatic deposition processes, andother dry powder application processes. Such coating procedures arewell-known in the art. Any coating process may be executed in such amanner as to prevent or limit to a minimal amount (for example, not morethan 5 wt %) removal of the composition within the lumens of the struttubes.

The coating may comprise a polymer, a therapeutic agent, and/or othermaterials. If a therapeutic agent is included in the coating, thetherapeutic agent may be the same as, or different from, the therapeuticagent of the composition in the lumens of the strut tubes. In someembodiments, the therapeutic agent of the composition within the struttubes may differ from the therapeutic agent in the coating only in thatit the one is a salt, hydrate, or polymorph of the other, or the two aredifferent salts or hydrates of the same chemical entity. In otherembodiments the therapeutic agent in the composition of the strut tubesmay be different chemical entities, that is the chemical entity havingthe pharmacological activity is different.

In preferred embodiments, the coating comprises a polymer, which may bea biostable polymer, a biodegradable polymer, or a combination thereof.The coating may comprise a primer layer free of, or essentially free of,therapeutic agents. The coating may also include other excipients.Non-limiting examples of such excipients include lubricating agents,fillers, plasticizing agents, surfactants, diluents, mold releaseagents, agents which act as therapeutic active agent carriers, binders,anti-tack agents, anti-foaming agents, viscosity modifiers,anti-oxidants, stabilizers, potentially residual levels of solvents, andpotentially any other agent which aids in, or may be desirable in, theprocessing of the material, and/or may be useful or desirable as acomponent of the final product. Surfactants may be used for thepreparation of a dispersion of polymer and/or therapeutic agent in asolvent or fluid.

Embodiments of the present invention encompass coatings in which thecoating layer, or materials included in the coating layer such as apolymer and/or therapeutic agents, are not covalently bound orchemically bound to the surface to which the coating is applied (thesubstrate surface, or a previously applied coating layer). Embodimentsalso encompass stents with a coating formed by the application of one ormore layers as described above, and includes stent with coatings inwhich one or more materials migrate from one layer to another eitherduring the coating application process and/or after the coatingapplication process has been completed.

Examples of polymers that may be used in the various embodiments of thepresent invention include, without limitation, poly(N-acetylglucosamine)(chitin); chitosan; poly(hydroxyvalerate); poly(hydroxybutyrate),poly(hydroxybutyrate-co-valerate); poly(3-hydroxybutyrate);poly(4-hydroxybutyrate); poly(3-hydroxyvalerate);poly(hydroxybutyrate-co-valerate); polyorthoesters; polyanhydrides;homopolymers of any of the following and random and block copolymers ofany combination of the following: D-lactic acid, L-lactic acid,DL-lactic acid, meso-lactide, caprolactone (including but not limitedto, ε-caprolactone), glycolide (glycolic acid), trimethylene carbonate,valeroactone, γ-undecalactone, β-methyl-δ-valerolactone, andhydroxycarboxylic acids (including, but not limited to, 3-hydroxybutyricacid, 4-hydroxybutyric acid, 3-hydroxyvaleric acid, 4-hydroxyvalericacid, 5-hydroxyvaleric acid, dimethylglycolic acid, β-hydroxypropanicacid, α-hydroxybutyric acid, α-hydroxycaproic acid, β-hydroxycaproicacid, γ-hydroxycaproic acid, δ-hydroxycaproic acid,δ-hydroxymethylcaproic acid, ε-hydroxycaproic acid, andε-hydroxymethylcaproic acid); poly(glycolide-co-caprolactone) polymers;poly(thioesters); polyethylene amide; polyester amide polymers;polyethylene acrylate; acrylate and methacrylate polymers;co-poly(ether-esters) (e.g., PEO/PLA); polyphosphazenes; biomolecules(e.g., fibrin, fibrinogen, cellulose, starch, collagen and hyaluronicacid); polyurethanes; silicones; polyesters; polyolefins;polyisobutylene and ethylene-alphaolefin copolymers; acrylic polymers;vinyl halide polymers and copolymers (e.g., polyvinyl chloride);polyvinyl ethers (e.g., polyvinyl methyl ether); polyvinylidene halides(e.g., polyvinylidene chloride); polyacrylonitrile; polyvinyl ketones;polyvinyl aromatics (e.g., polystyrene); polyvinyl esters (e.g.,polyvinyl acetate); acrylonitrile-styrene copolymers; ABS resins;polyamides (e.g., Nylon 66 and polycaprolactam); polycarbonates;polyoxymethylenes; polyimides; polyethers; rayon; rayon-triacetate;cellulose and derivatives thereof and copolymers thereof (includingwithout limitation cellulose acetate, cellulose butyrate, celluloseacetate butyrate, cellophane, cellulose nitrate, cellulose propionate,cellulose ethers, and carboxymethyl cellulose); and any copolymers andany blends of the aforementioned polymers.

Additional representative examples of polymers for use in the variousembodiments of the present invention include, without limitation,ethylene vinyl alcohol copolymer (commonly known by the generic nameEVOH or by the trade name EVAL™); poly(butyl methacrylate);poly(vinylidene fluoride-co-hexafluoropropylene) (e.g., SOLEF® 21508,available from Solvay Solexis PVDF of Thorofare, N.J.); polyvinylidenefluoride (otherwise known as KYNAR™, available from Atofina Chemicals ofPhiladelphia, Pa.);poly(tetrafluoroethylene-co-hexafluoropropylene-co-vinylidene fluoride);ethylene-vinyl acetate copolymers; and polyethylene glycol; andcopolymers and combinations thereof.

As used herein, the terms poly(D,L-lactide) (PDLL), poly(L-lactide)(PLL), poly(D,L-lactide-co-glycolide) (PDLLG), andpoly(L-lactide-co-glycolide) (PLLG) are used interchangeably with theterms poly(D,L-lactic acid) (PDLLA), poly(L-lactic acid) (PLLA),poly(D,L-lactic acid-co-glycolic acid) (PDLLAGA), and poly(L-lacticacid-co-glycolic acid) (PLLAGA), respectively.

Any of the above polymers or materials specifically listed may be usedindividually and/or in combination with any other polymer and/ormaterials listed herein. Likewise, therapeutic agents may be combined orused individually.

Various embodiments of the current invention encompass bothuncross-linked and cross-linked polymers, branched and unbranchedpolymers, and dendritic polymers. In preferred embodiments, the polymersused may be uncross-linked or not crosslinked.

EXAMPLES

The following examples are given to aid in understanding the invention,but it is to be understood that the invention is not limited to theparticular materials, apparatus, or procedures of the examples.

Example 1 Prospective Example

An 18 mm in length stent with hollow struts is fabricated from abiocompatible metal such as stainless steel. PEG 1000 having anumber-average molecular weight of about 1000 Daltons is melted at atemperature at or above 45° C. Zotarolimus is dissolved into the PEG1000 forming a composition of 90% by weight PEG 1000 and 10% by weightzotarolimus. The stent is pre-heated to a temperature of about 45° C.,and maintained at 45° C. or slightly higher while the composition, whichis also maintained at 45° C. or a higher temperature, is injected intothe lumen of the struts. A sufficient volume to provide 180 ug ofzotarolimus is injected. If the volume of the strut lumens is notsufficient to obtain 180 ug of zotarolimus at a weight ratio of PEG 1000to zotarolimus of 9:1, the weight ratio may be adjusted slightly suchthat the stent contains 180 ug of zotarolimus.

Example 2 Prospective Example

Dexamethasone acetate, with a melting temperature of 240° C., is meltedto form a composition which is injected into the lumen of a 12 mm stenthaving hollow struts. The injector is coupled to an inlet opening of thetube forming the stent until the composition is visible at the other endof the tube. The filled stent is cooled to about 20° C. to 25° C. Thedexamethasone acetate solidifies.

Example 3 Prospective Example

The stent from example 2, after being loaded with dexamethasone acetate,is coated by spray coating. The coating is obtained by spraying a 1:1weight ratio blend of zotarolimus and poly(glycolide-co-D,L-lactide), ofa 75:25 molar ratio of the constituent monomers glycolide:D,L lactide,in acetone onto the outer surface of the stent such that 120 ug ofzotarolimus is contained in the resulting coating on the stent. When thestent is implanted, the zotarolimus is first released to control smoothmuscle cell proliferation. After about 1 to 3 months, the stent beginsto release dexamethasone acetate which is released over an extendedperiod of time providing an anti-inflammatory effect.

Example 4 Prospective Example

A composition is obtained by dissolving zotarolimus in the solventHFC-134a™ (CF₃CFH₂) at a weight ratio of 1:2 zotarolimus to solvent. Bymaintaining the temperature less than −30° C. or the pressure at orabove 40 psi, the composition is in a liquid state. An 18 mm stent withhollow struts is injected with the composition while maintaining eitherthe pressure at or above 40 psi (gauge) and/or the temperature less than−30° C. so that the composition remains in a liquid state during theinjection. After the stent is loaded or filled with the composition, thepressure is altered to about one atmosphere (˜14.7 psi absolute). As aresult of the pressure change, the solvent evaporates and escapesthrough the holes and/or openings in the stent. As a result 180 ug ofzotarolimus is deposited within the lumen of the stent struts and thereis no residual solvent, or a very low quantity of residual solvent dueto the high vapor pressure of the solvent.

Example 5 Prospective Example

A composition is made by dissolving or dispersing zotarolimus in PEG400, that is a poly(ethylene glycol) having a number-average molecularweight of about 400 and which is a liquid at a temperature of 25° C. anda pressure of one atmosphere. The composition formed is paste-like inconsistency. About 300 ug of the paste is injected into a stent havinghollow struts, specifically into the lumen of the hollow struts. Theresult is a stent containing 150 ug of zotarolimus.

Example 6 Prospective Example

A composition is made by dissolving zotarolimus in Capmul MCM EP,glycerol monocaprylocaprate (Abitec Corp Janesville, Wis.) at a weightratio of 1/1. The composition forms a flowable, high viscosity fluid. An18 mm stent with hollow struts is immersed in the composition.Application of vacuum, while heating at 45° C., followed by releasingthe pressure to ambient fills the strut tubes with the composition. Theresult is a stent containing about 180 ug of zotarolimus.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects. Therefore, the claims are to encompasswithin their scope all such changes and modifications as fall within thetrue spirit and scope of this invention. Moreover, although individualaspects or features may have been presented with respect to oneembodiment, a recitation of an aspect for one embodiment, or therecitation of an aspect in general, is intended to disclose its use inall embodiments in which that aspect or feature can be incorporatedwithout undue experimentation. Also, embodiments of the presentinvention specifically encompass embodiments resulting from treating anydependent claim which follows as alternatively written in a multipledependent form from all prior claims which possess all antecedentsreferenced in such dependent claim (e.g. each claim depending directlyfrom claim 1 should be alternatively taken as depending from anyprevious claims).

What is claimed is:
 1. A method of loading a composition into astructural element of a stent, comprising: providing a stent comprisinga structural element or providing a structural element that is to beused in forming a stent, the structural element defined by a lumen andat least one opening to access the lumen; providing a container filledwith the composition, the composition comprising a therapeutic agent;wherein the composition is in a fluid state in the container, and thecomposition has characteristics such that when the composition is at atemperature of 30° C. and at one atmosphere, the composition is in asolid state or semi-solid state or in a fluid state with a viscosity ofabout 10 cP or greater than 10 cP; or the composition hascharacteristics such that when the composition is at a temperature of20° C. to 30° C. and a pressure of one atmosphere, the viscosity of thecomposition is greater than 10 cP or about 10 cP; heating the structuralelement to a temperature of about 30° C. to about 60° C.; after heatingthe structural element, immersing the structural element into thecomposition; and allowing the composition to fill the lumen.
 2. Themethod of claim 1, further comprising, after allowing the composition tofill the lumen, removing the structural element from the composition. 3.The method of claim 2, further comprising, sealing the access openingwhen the structural element is removed from the composition to preventthe composition from escaping out from the lumen.
 4. The method of claim1, further comprising rinsing the structural element to at leastpartially remove the composition comprising the therapeutic agent on anouter surface of the structural element such that the rinsing act doesnot remove the composition comprising the therapeutic agent from withinthe lumen.
 5. The method of claim 1, wherein the structural element is atube such that the access opening is positioned at one end of the tubeand the tube further comprises a plurality of discharge openings about asurface of the tube to allow discharge of the composition comprising thetherapeutic agent from the structural element after implantation of thestent in a patient.
 6. The method of claim 5, additionally comprising,prior to the immersion, attaching a conduit to the access opening, andapplying a vacuum through the access opening via the conduit when thestructural element is immersed in the composition to draw thecomposition through the discharge openings into the lumen.
 7. The methodof claim 5, wherein each of the discharge openings is at most 50% of thesize of the access opening.
 8. The method of claim 1, wherein thecomposition is free of, or essentially free of, solvents, and thecomposition is in a fluid state in the container, and the compositionhas characteristics such that when the composition is at a temperatureof 30° C. and at one atmosphere, the composition is in a solid state ora semi-solid state or in a fluid state with a viscosity of about 10 cPor greater than 10 cP.
 9. The method of claim 8, wherein the compositionconsists essentially of the therapeutic agent.
 10. The method of claim9, wherein the therapeutic agent is relatively stable or stable whenmelted.
 11. The method of claim 9, wherein the therapeutic agent isselected from the group consisting of paclitaxel, protaxel,dexamethasone, momentasone, clobetasol, dexamethasone acetate, and allcombinations thereof in all proportions.
 12. The method of claim 1,further comprising, after allowing the composition to fill the lumen,cooling the structural element.
 13. The method of claim 12, wherein thetherapeutic agent is temperature sensitive.
 14. The method of claim 12,wherein the therapeutic agent is not stable at temperatures of about 60°C. and greater than 60° C.
 15. The method of claim 12, wherein thetherapeutic agent is selected from the group consisting of zotarolimus,everolimus, sirolimus, biolimus, ridaforolimus, novolimus, myolimus,temsirolimus, and all combinations thereof in all proportions.
 16. Themethod of claim 12, wherein the excipient is selected from the groupconsisting of solid poloxamers, polysorbate 60, Vitamin E TGPS, di-blockand tri-block polymers formed from ethylene oxide and propylene oxide,Poloxamer 188, Poloxamer 407, ascorbyl palmitate, lecithin, egg yolkphospholipid, phosphatidylcholine, polyethylene glycol-phosphatidylethanolamine conjugate (PEG-PE), polyethylene glycol, triglycerides,diglycerides, monoglycerides, fatty alcohols, and all combinationsthereof in all proportions.
 17. The method of claim 1, wherein thecomposition is free of, or essentially free of, solvents, and thecomposition is in a fluid state in the container, and the compositionhas characteristics such that when the composition is at a temperatureof 30° C. and at one atmosphere, the composition is in a solid state ora semi-solid state or in a fluid state with a viscosity of not less than100 cP.
 18. The method of claim 1, wherein the composition is free of,or essentially free of, solvents, and the composition is in a fluidstate in the container, and the composition has characteristics suchthat when the composition is at a temperature of 30° C. and at oneatmosphere, the composition is in a solid state or a semi-solid state.19. The method of claim 18, wherein the composition comprises anexcipient.
 20. The method of claim 19, wherein the therapeutic agent isdispersed in the excipient.
 21. The method of claim 19, wherein thecomposition comprises microspheres, nanoparticles, microparticles,microshells, or a combination thereof which comprise the therapeuticagent.
 22. The method of claim 1, further comprising after allowing thecomposition to fill the lumen, cooling the structural element.
 23. Themethod of claim 1, wherein the composition is free of, or essentiallyfree of, solvents, and the composition has characteristics such thatwhen the composition is at a temperature of 20° C. to 30° C. and apressure of one atmosphere, the viscosity of the composition is greaterthan 100 cP or about 100 cP.